Short bioactive peptides

ABSTRACT

Short bioactive peptides containing phenylalanine, leucine, alanine, and lysine residues are disclosed. The peptides can be used in antibacterial, antifungal, anticancer, and other biological applications.

FIELD OF THE INVENTION

[0001] The invention relates to short length peptides containingphenylalanine, leucine, alanine, and lysine amino acid residues (F, L,A, and K; “FLAK peptides”) in their primary sequence. In particular,FLAK peptides having desirable antimicrobial, antifungal, anticancer,and other biological activities are disclosed.

BACKGROUND OF THE INVENTION

[0002] Various bioactive peptides have been reported in both thescientific literature and in issued patents. Peptides historically havebeen isolated from natural sources, and have recently been the subjectof structure-function relationship studies. Additionally, naturalpeptides have served as starting points for the design of syntheticpeptide analogs.

[0003] A review of peptide antibiotics was published by R. E. W. Hancockin 1997 (Lancet 349: 418-422). The structure, function, and clinicalapplications of various classes of peptides were discussed. Anadditional review of cationic peptide antibiotics was published in 1998(Hancock, R. E. W. and Lehrer, R. Trends Biotechnol. 16: 82-88). Thepeptides are typically cationic amphipathic molecules of 12 to 45 aminoacids in length. The peptides permeabilize cell membranes leading to thecontrol of microbial agents. The clinical potential of host defensecationic peptides was discussed by R. E. W. Hancock in 1999 (Drugs57(4): 469-473; Antimicrobial Agents and Chemotherapy 43(6): 1317-1323).The antibacterial, antifungal, antiviral, anticancer, and wound healingproperties of the class of peptides are discussed.

[0004] Reviews of the structural features of helical antimicrobialpeptides, and their presumed mechanisms of action have been published(see, for example, Dathe, M. and Wieprecht, T. Biochimica et BiophysicaActa 1462: 71-87 (1999); Epand, R. M. and Vogel H. J. Biochimica etBiophysica Acta 1462: 11-28 (1999)). Structural parameters believed tobe capable of modulating activity and selectivity include helicity,hydrophobic moment, hydrophobicity, angle subtended by thehydrophilic/hydrophobic helix surfaces, and charge.

[0005] A wide array of naturally occurring alpha helical peptides havebeen reported. The following are representative of the many referencesin the field.

[0006] Cecropins are a family of α-helical peptides isolated frominsects. Cecropins are known for their antibacterial properties, asdescribed in U.S. Pat. Nos. 4,355,104 and 4,520,016. The cecropins weregenerally found to have activity against gram-negative bacteria, but notagainst all gram-negative bacteria. Cecropins were found not to haveactivity against eucaryotic cells (Andreu, et al., Biochemistry 24:163-188 (1985); Boman, et al., Developmental and Comparative Immunol. 9:551-558 (1985); Steiner et al., Nature 292: 246-248 (1981)). Cecropinsfrom Drosophila and Hyalphora were presented as having activity againstvarious strains of fungi (Ekengren, S. and Hultmark, D., Insect Biochem.and Molec. Biol. 29: 965-972 (1999)). Cecropin A from mosquito Aedesaegypti is reportedly different from most insect cecropins in that itlacks tryptophan and C-terminal amidation (Lowenberger, C. et al., J.Biol Chem. 274(29): 20092-20097 (1999)).

[0007] Frogs from the genus Rana produce a wide array of antimicrobialpeptides in their skin (Goraya, J. et al., Eur. J Biochem. 267: 894-900(2000)). Peptides as short as 13 amino acids were reported, and weregrouped into structural families. The sequences showed little or nosequence identity to peptides isolated from frogs of other genera, suchas the magainin and dermaseptin peptides.

[0008] U.S. Pat. No. 5,962,410 disclosed the inhibition of eucaryoticpathogens, and the stimulation of lymphocytes and fibroblasts with lyticpeptides such as cecropins and sarcotoxins. Various peptides presentedinclude Cecropin B, Cecropin SB-37, Cecropin A, Cecropin D, Shiva-1,Lepidopteran, Sarcotoxin 1A, Sarcotoxin 1B, and Sarcotoxin 1C.

[0009] Transgenic mice producing the Shiva-1 cecropin class lyticpeptide were reported by Reed, W. A. et al., Transgenic Res. 6: 337-347(1997). Infection of the transgenic mice with a Brucella abortuschallenge resulted in a reduction of the number of bacteria relative toinfection of non-transgenic mice.

[0010] Magainin is an α-helical 23 amino acid peptide isolated from theskin of the African frog Xenopus laevis (Zasloff, M. Proc. Natl. Acad.Sci. U.S.A. 84: 5449-5453 (1987).

[0011] Cathelin associated α-helical peptides of 23 to 38 amino acidsare found in the blood cells of sheep, humans, cattle, pigs, mice, andrabbits (Zanetti, M. et al., FEBS Lett. 374: 1-5 (1995)).

[0012] The antimicrobial activities of buforin II, cecropin P1,indolicidin, magainin II, nisin, and ranalexin were reported byGiacomette, A. et al. (Peptides 20: 1265-1273 (1999)). The peptidesshowed variable activities against bacteria and yeast.

[0013] Various synthetic peptides have been prepared and assayed both invitro and in vivo.

[0014] U.S. Pat. No. 5,861,478 disclosed synthetic lytic peptides ofabout 20 to 40 amino acids which adopt an α-helical conformation. Thepeptides are effective in the treatment of microbial infections, wounds,and cancer. The peptides disclosed include cecropin B, SB-37*, LSB-37,SB-37, Shiva 1 and 10-12, β-fibrin signal peptide, Manitou 1-2, Hecate1-3, Anubis 1-5 and 8, and Vishnu 1-3 and 8.

[0015] Hecate was described as a synthetic peptide analog of melittin byBaghian, A. et al. (Peptides 18(2): 177-183 (1997)). The peptides differin their charge distribution, but not in their amphipathic alpha helicalconformation. Hecate inhibited herpes simplex virus (HSV-1) while notadversely affecting cell growth and protein synthesis.

[0016] Synthetic peptides D2A21, D4E1, D2A22, D5C, D5CI, D4E, and D4Bwere described in Schwab, U. et al., Antimicrob. Agents and Chemotherapy43(6): 1435-1440 (1999). Activities against various bacterial strainswere presented.

[0017] Hybrid peptides made of cecropin and melittin peptides werereportedly prepared and assayed by Juvvadi, P. et al. (J. Peptide Res.53: 244-251 (1999)). Hybrids were synthesized to investigate the effectsof sequence, amide bond direction (helix dipole), charge,amphipathicity, and hydrophobicity on channel forming ability and onantibacterial activity. Sequence and amide bond direction were suggestedto be important structural requirements for the activity of the hybrids.

[0018] A 26 amino acid insect cecropin—bee melittin hybrid, and analogsthereof, were described in a study of salt resistance (Friedrich, C. etal., Antimicrobial Agents and Chemotherapy 43(7): 1542-1548 (1999)). Atryptophan residue in the second position was found to be critical foractivity. Modest changes in sequence were found to lead to substantialchanges in the properties of the peptides.

[0019] The effects of proline residues on the antibacterial propertiesof α-helical peptides has been published (Zhang, L. et al., Biochem. 38:8102-8111 (1999)). The addition of prolines was reported to change themembrane insertion properties, and the replacement of a single prolinemay change an antimicrobial peptide into a toxin.

[0020] A series of peptides having between 18 and 30 amino acids wereprepared in order to test the effects of changes in sequence and chargeon antibacterial properties (Scott, M. G., et al., Infect. Immun. 67(4):2005-2009 (1999)). No significant correlation was found between length,charge, or hydrophobicity and the antimicrobial activity of thepeptides. A general trend was found that shorter peptides were lessactive than longer peptides, although the authors expressed that thiseffect would probably be sequence dependent.

[0021] “Modellins”, a group of synthetic peptides were prepared andassayed to compare sequence and structure relationships (Bessalle, R. etal. J. Med. Chem. 36: 1203-1209 (1993)). Peptides of 16 and 17 aminoacids having hydrophobic and hydrophilic opposite faces were highlyhemolytic and antibacterial. Smaller peptides tended to have lowerbiological activities.

[0022] A cecropin-melittin hybrid peptide and an amidated flounderpeptide were found to protect salmon from Vibrio anguillarum infectionsin vivo (Jia, X. et al., Appl. Environ. Microbiol. 66(5): 1928-1932(2000)). Osmotic pumps were used to deliver a continuous dose of eitherpeptide to the fish.

[0023] Amphipathic peptides have been reported as being capable ofenhancing wound healing and stimulating fibroblast and keratinocytegrowth in vivo (U.S. Pat. Nos. 6,001,805 and 5,561,107). Transgenicplants have been reportedly prepared expressing lytic peptides as afusion protein with ubiquitin (U.S. Pat. No. 6,084,156). Methylatedlysine rich lytic peptides were reportedly prepared, displaying improvedproteolytic resistance (U.S. Pat. No. 5,717,064).

[0024] While a number of natural and synthetic peptides exist, thereexists a need for improved bioactive peptides and methods for their use.

SUMMARY OF THE INVENTION

[0025] Short (i.e. no more than 23 amino acids in length) peptidescontaining phenylalanine, leucine, alanine, and lysine amino acidresidues in their primary sequence are disclosed. The peptides displaydesirable antibacterial, antifungal, anticancer biological activities,and also cause stimulation and proliferation of human fibroblasts andlmphocytes.

Description of the Sequence Listings

[0026] The following sequence listings form part of the presentspecification and are included to further demonstrate certain aspects ofthe present invention. The invention may be better understood byreference to one or more of these sequences in combination with thedetailed description of specific embodiments presented herein. TABLE 1P- SEQ ID NO: Name No. Primary sequence 1 Hecate AC #1010 1FALALKALKKALKKLKKALKKAL-COOH 2 Hecate AM 2 FALALKALKKALKKLKKALKKAL-NH2 3SB-37 AC #1018 5 MPKWKVFKKIEKVGRNIRNGIVKAGPAIAVLGEAKALG- COOH 4 Shiva 10AM 11 FAKKLAKKLKKLAKKLAKLALAL-NH2 5 SB-37 AM 12MPKWKVFKKIEKVGRNIRNGIVKAGPAIAVLGEAKALG- NH2 6 Shiva 10 AC #1015 13FAKKLAKKLKKLAKKLAKLALAL-COOH 7 Magainin 2 16 GIGKFLHSAKKFGKAFVGGIMNS-NH28 FLAK01 AM 23 FALAAKALKKLAKKLKKLAKKAL-NH2 9 FLAK03 AM 24FALALKALKKLLKKLKKLAKKAL-NH2 10 FLAK04 AM 25 FALALKALKKLAKKLKKLAKKAL-NH211 FLAK05 AM 26 FALAKLAKKAKAKLKKALKAL-NH2 12 FLAK06 AM 27FALALKALKKLKKALKKAL-NH2 13 FLAK06 AC 27 FALALKALKKLKKALKKAL-COOH B 14FLAK06 R-AC 27 FAKKLAKKLKKLAKLALAL-COOH C 15 KAL V 30VALALKALKKALKKLKKALKKAL-NH2 16 FLAK 17 AM 34 FALALKKALKALKKAL-NH2 17FLAK 26 AM 35 FAKKLAKLAKKLAKLAL-NH2 18 FLAK 25 AM 36FAKKLAKLAKKLAKLALAL-NH2 19 Hecate 2DAc 37FALALKALKKAL-(D)-K-(D)-KLKKALKKAL-COOH 20 FLAK43 AM 38FAKKIAKLAKKLLAL-NH2 21 FLAK44 AM 39 FAKKLAKLAKKALAL-NH2 22 FLAK62 AM 40FALAKKALKKAKKAL-NH2 23 FLAK 06R-AM 41 FAKKLAKKLKKLAKLALAK-NH2 24 MSI-78AM 42 GIGKFLKKAKKFGKAFVKILKK-NH2 25 FLAK50 43 FAKLLAKLAKKLL-NH2 26FLAK51 44 FAKKLAKLALKLAKL-NH2 27 FLAK57 45 FAKKLAKKLAKLAL-NH2 28 FLAK7146 FAKKLKKLAKLAKKL-NH2 29 FLAK77 47 FAKKALKALKKL-NH2 30 FLAK50V 48VAKLLAKLAKKLL-NH2 31 FLAK50F 49 FAKLLAKLAKKL-NH2 32 FLAK26V AM 50VAKKLAKLAKKLAKLAL-NH2 33 CAME-15 53 KWKLFKKIGAVLKVL-NH2 34 FLAK50C 54FAKLLAKLAKKAL-NH2 35 FLAK50D 55 FAKLLAKALKKLL-NH2 36 FLAK 50E 56FAKLLKLAAKKLL-NH2 37 FLAK80 57 FAKLLAKKLL-NH2 38 FLAK81 58FAKKLAKALL-NH2 39 FLAK82 59 FAKKLAKKLL-NH2 40 FLAK83M 60 FAKLAKKLL-NH241 FLAK 26 Ac 61 FAKKLAKLAKKLAKLAL-COOH 42 Indolicidin 63ILPWKWPWWPWRR-NH2 43 FLAK 17C 64 FAKALKALLKALKAL-NH2 44 FLAK 50H 65FAKLLAKLAKAKL-NH2 45 FLAK 50G 66 FAKLLAKLAKLKL-NH2 46 Shiva Deriv 70FAKKLAKKLKKLAKKLAKKWKL-NH2 P69+KWKL 47 Shiva 10(1-18 AC) 71FAKKLAKKLKKLAKKLAK-COOH 48 Shiva 10 peptide 72FAKKLAKKLKKLAKKLAKKWKL-COOH 71+KWKL 49 CA(1-7)Shiva10(1- 73KWKLFKKKTKLFKKFAKKLAKKL-NH2 16) 50 FLAK 54 74 FAKKLAKKLAKAL-NH2 51 FLAK56 75 FAKKLAKKLAKLL-NH2 52 FLAK 58 76 FAKKLAKKLAKAAL-NH2 53 FLAK 72 77FAKKLAKKAKLAKKL-NH2 54 FLAK 75 79 FAKKLKKLAKKL-NH2 55 Shiva 10 (1-16) Ac80 KTKLFKKFAKKLAKKLKKLAKKL-COOH 56 CA(1-7)Shiva10 81KWKLFKKKTKLFKKFAKKLAKKL-COOH (1-16)-COOH 57 Indolocidin-ac 91ILPWKWPWWPWRR-COOH 58 FLAK50B 92 FAKALAKLAKKLL-NH2 59 FLAK50J 93FAKLLAKLAKKAA-NH2 60 FLAK50I 94 FAKLLALALKLKL-NH2 61 FLAK50K 95FAKLLAKLAKAKA-NH2 62 FLAK50L 96 FAKLLAKLAKAKG-NH2 63 Shiva-11 98FAKKLAKKLKKLAKKLAKLALALKALALKAL-NH2 64 Shiva 11 99FAKKLAKKLKKLAKKLIGAVLKV-COOH [(1-16)ME(2-9]- COOH 65 FLAK 50N 101FAKLLAKALKLKL-NH2 66 FLAK 50O 102 FAKLLAKALKKAL-NH2 67 FLAK 50P 103FAKLLAKALKKL-NH2 68 CA(1- 104 KWKLFKKALKKLKKALKKAL-NH2 &Hecate(11/23) 69PYL-ME 105 KIAKVALAKLGIGAVLKVLTTGL-NH2 70 FLAG26-D1 106 FAKKLAKLAKKL-NH271 Vishnu3 107 MPKEKVFLKIEKMGRNIRN-NH2 72 Melittin 108GIGAVLKVLTTGLPALISWIKRKRQQ-NH2 73 FLAK26-D2 109 FAKKLAKLAKKLAKAL-NH2 74FLAG26-D3 110 FAKKLLAKALKL-NH2 75 FLAK50 Q1 111 FAKFLAKFLKKAL-NH2 76FLAK50 Q2 112 FAKLLFKALKKAL-NH2 77 FLAK50 Q3 113 FAKLLAKFLKKAL-NH2 78FLAK50 Q4 114 FAKLLAKAFKKAL-NH2 79 FLAK50 Q5 117 FAKLFAKAFKKAL-NH2 80FLAK50 Q6 118 FAKLLAKALKKFL-NH2 81 FLAK50 Q7 119 FAKLLAKALKKFAL-NH2 82FLAK50 Q8 120 FAKLLAKLAKKFAL-NH2 83 FLAK50 Q9 121 FAKLFAKLAKKFAL-NH2 84FLAK50 Q10 122 FKLAFKLAKKAFL-NH2 85 FLAK50 T1 123 FAKLLAKLAK-NH2 86FLAK50 T2 124 FAKLLAKLAKKVL-NH2 87 FLAK50 T3 125 FAKLLAKLAKKIL-NH2 88FLAK50 T4 126 FAKLLAKLAKKEL-NH2 89 FLAK50 T5 127 FAKLLAKLAKKSL-NH2 90FLAK90 128 FAKLA-NH2 91 FLAK91 129 FAKLF-NH2 92 FLAK92 130 KAKLF-NH2 93FLAK93 131 KWKLF-NH2 94 FLAK50 Z1 132 FGKGIGKVGKKLL-NH2 95 FLAK50 Z2 133FAFGKGIGKVGKKLL-NH2 96 FLAK50 Z3 134 FAKAIAKIAFGKGIGKVGKKLL-NH2 97FLAK50 Z4 135 FAKLWAKLAFGKGIGKVGKKLL-NH2 98 FLAK50 Z5 136FAKLWAKLAKKL-NH2 99 FLAK50 Z6 137 FAKGVGKVGKKAL-NH2 100 FLAK50 Z7 138FAFGKGIGKIGKKGL-NH2 101 FLAK50 Z8 139 FAKIIAKIAKIAKKIL-NH2 102 FLAK50 Z9140 FAFAKIIAKIAKKII-NH2 103 FLAK94 141 FALALKA-NH2 104 FLAK93B 142KWKLAKKALALL-NH2 105 FLAK50 Z10 143 FAKIIAKIAKKI-NH2 106 FLAK96 144FALALKALKKAL-NH2 107 FLAK97 145 FALKALKK-NH2 108 FLAK98 146KYKKALKKLAKLL-NH2 109 FKRLA 147 FKRLAKIKVLRLAKIKR-NH2 110 FLAK91B 148FAKLAKKALAKLL-NH2 111 FLAK92B 149 KAKLAKKALAKLL-NH2 112 FLAK99 150KLALKLALKALKAAKLA-NH2 113 FLAK50T6 151 FAKLLAKLAKK-NH2 114 FLAK50T7 152FAKLLAKLAKKGL-NH2 115 FLAK95 153 FALKALKKLKKALKKAL-NH2 116 FLAK50T8 154VAKLLAKLAKKVL-NH2 117 FLAK50T9 155 YAKLLAKLAKKAL-NH2 118 FLAK100-CO2H156 KLLKLLLKLYKKLLKLL-COOH 119 FAGVL 157 FAVGLRAIKRALKKLRRGVRKVAKDL-NH2120 Modelin-5 159 KLAKKLAKLAKLAKAL-NH2 121 Modelln-5-CO2H 160KLAKKLAKLAKLAKAL-COOH 122 Modelin-8 161 KWKKLAKKW-NH2 123 Modelin-8-CO2H162 KWKKLAKKW-COOH 124 Modelin-1 163 KLWKKWAKKWLKLWKAW-NH2 125Modelin-1-CO2H 164 KLWKKWAKKWLKLWKA-COOH 126 FLAK120 165 FALALKALKKL-NH2127 FLAK121 166 FALAKALKKAL-NH2 128 FLAK96B 167 FALALKLAKKAL-NH2 129FLAK96G 168 FALLKL-NH2 130 FLAK96F 169 FALALKALKK-NH2 131 FLAK96C 170FALKALKKAL-NH2 132 FLAK96D 171 FALLKALKKAL-NH2 133 Modelin-8B 172KWKK-NH2 134 Modelin-8C 173 KWKKL-NH2 135 Modelin-8D 174 KFKKLAKKF-NH2136 Modelin-8E 175 KFKKLAKKW-NH2 137 Flak 96 176 FALALKALKKA-NH2 138Flak 96I 177 FALLKALLKKAL-NH2 139 Flak 96J 178 FALALKLAKKL-NH2 140 Flak96L 179 LKKLAKLALAF-NH2 141 FLAK-120G 180 VALALKALKKL-NH2 142 FLAK-120D181 FALALKLKKL-NH2 143 FLAK-120C 182 FALALKAKKL-NH2 144 FLAK-120B 183FALA-NH2 145 FLAK-120F 184 WALAL-NH2 146 Magainin2wisc 300GIGKFLHAAKKFAKAFVAEIMNS-NH2 147 D2A21 301 FAKKFAKKFKKFAKKFAKFAFAF-NH2148 KSL-1 302 KKVVFKVKFK-NH2 149 KSL-7 303 FKVKFKVKVK-NH2 150 LSB-37 306LPKWKVFKKIEKVGRNIRNGIVKAGPIAVLGEAKALG- NH2 151 Anubis-2 307FAKKLAKKLKKLAKKLAKLAKKL-NH2 152 FLAK17CV 501 VAKALKALLKALKAL-NH2 153FLAK50Q1V 502 VAKFLAKFLKKAL-NH2 154 D2A21V 503VAKKFAKKFKKFAKKFAKFAFAF-NH2 155 FLAK25AMV 504 VAKKLAKLAKKLAKLALAL-NH2156 FLAK43AMV 505 VAKKLAKLAKKLLAL-NH2 157 FLAK50DV 506 VAKLLAKALKKLL-NH2158 HECATE AMV 507 VALALKALKKALKKLKKALKKAL-NH2 159 HECATE ACV 508VALALKALKKALKKLKKALKKAL-COOH 160 FLAK04AMV 509VALALKALKKLAKKLKKLAKKAL-NH2 161 FLAK03AMV 510VALALKALKKLLKKLKKLAKKAL-NH2 162 D-Shiva 10 AC 67(D)-FAKKLAKKLKKLAKKLAKLALAL-COOH 163 Shiva 11 AC 100FAKKLAKKLKKLAKKLAKLALALKALALKA-COOH 164 Shiva 10 (1-18)AM 69FAKKLAKKLKKLAKKLAK-NH2 165 FLAK 50M 97 FAKLLALALKKAL-NH2

DETAILED DESCRIPTION OF THE INVENTION

[0027] The invention is generally directed towards peptides havingdesirable biological properties, and their use. It is surprising thatthe peptides are efficacious due to their short length as compared toother peptides described in the art.

[0028] Peptides

[0029] One embodiment of the invention is directed towards an isolatedpeptide comprising phenylalanine, leucine, alanine, and lysine residues,wherein the peptide is about 5 to about 23 amino acids in length. Thepeptide can have a minimum length of about 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, or about 18 amino acids. The peptide can have amaximum length of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, or about 23 amino acids. The peptide can be about 5to about 20 amino acids in length. The peptide can consist essentiallyof, or consist of phenylalanine, leucine, alanine, and lysine residues.The peptide can have a percent amino acid composition of phenylalanine,leucine, alanine, and lysine residues of at least about 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%. Thepeptide can generally be any of the listed SEQ ID NOS which fall withinthese various guidelines, and more preferably is SEQ ID NO:1, SEQ IDNO:2, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10,SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ IDNO:23, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ IDNO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ IDNO:35, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ IDNO:46, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:55, SEQ IDNO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ IDNO:61, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ IDNO:71, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:80, SEQ IDNO:81, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ IDNO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:106, SEQ IDNO:108, SEQ ID NO:112, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:126, SEQID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:131, SEQ ID NO:132,SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ IDNO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQID NO:152, SEQ ID NO:159, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164,and SEQ ID NO:165. The peptide is preferably not hecate-1, anubis-1,anubis-2, anubis-5, anubis-8, vishnu-1, vishnu-2, vishnu-3, vishnu-8, orshiva-10.

[0030] The peptide can be similar to any of the above describedpeptides, and preferably is similar to SEQ ID NO:2 (or SEQ ID NO:16 orSEQ ID NO:126), SEQ ID NO:4 (or SEQ ID NO:14 or SEQ ID NO:17), SEQ IDNO:25, SEQ ID NO:43, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:115, or SEQID NO:132 as determined by percent identity. The percent identitybetween the peptides is preferably at least about 70%, 75%, 80%, 85%,90%, 95%, 96%, 97%, 98%, 99%, or 100%. Percent identity is determinedusing a sequence alignment by the commercial product CLUSTALW. Thenumber of aligned amino acids are divided by the length of the shorterpeptide, and the result is multiplied by 100% to determine percentidentity. If the length of the shorter peptide is less than 10 aminoacids, the number of aligned amino acids are divided by 10, and theresult is multiplied by 100% to determine percent identity.

[0031] The peptides can comprise D- or L- amino acids. The peptides cancomprise all D- amino acids. The peptides can have an acid C-terminus(—CO₂H) or an amide C-terminus (—CONH₂, —CONHR, or —CONR₂).

[0032] Methods of use

[0033] An additional embodiment of the invention is directed towardsmethods of using the above described peptides. The methods of usepreferably do not cause injury or kill normal uninfected mammaliancells. The methods of use at therapeutic dose levels preferably do notcause injury to or kill normal uninfected or non-neoplastic mammaliancells. The methods of use may involve the use of a single peptide, ormay involve the use of multiple peptides.

[0034] An embodiment of the invention is the use of the above describedpeptides to inhibit or kill microbial cells (microorganisms). Themicroorganisms may be bacterial cells, fungal cells, protozoa, viruses,or eucaryotic cells infected with pathogenic microorganisms. The methodgenerally is directed towards the contacting of microorganisms with thepeptide. The contacting step can be performed in vivo, in vitro,topically, orally, transdermally, systemically, or by any other methodknown to those of skill in the art. The contacting step is preferablyperformed at a concentration sufficient to inhibit or kill themicroorganisms. The concentration of the peptide can be at least about0.1 μM, at least about 0.5 μM, at least about 1 μM, at least about 10μM, at least about 20 μM, at least about 50 μM, or at least about 100μM. The methods of use can be directed towards the inhibition or killingof microorganisms such as bacteria, gram positive bacteria, gramnegative bacteria, mycobacteria, yeast, fungus, algae, protozoa,viruses, and intracellular organisms. Specific examples include, but arenot limited to, Staphylococcus, Staphylococcus aureus, Pseudomonas,Pseudomonas aeruginosa, Escherichia coli, Chlamydia, Candida albicans,Saccharomyces, Saccharomyces cerevisiae, Schizosaccharomyces pombe,Trypanosoma cruzi, or Plasmodium falciparum. The contacting step can beperformed by systemic injection, oral, subcutaneous, IP, IM, IVinjection, or by topical application. For injection, the dosage can bebetween any of the following concentrations: about 1 mg/kg, about 5mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg,and about 100 mg/kg. The contacting step can be performed on a mammal, acat, a dog, a cow, a horse, a pig, a bird, a chicken, a plant, a fish,or a human.

[0035] Preferred peptides for antibacterial applications include SEQ IDNO:1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10,SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15,SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20,SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28,SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35,SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46,SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:55, SEQ ID NO:56,SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:66,SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:77,SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:87,SEQ ID NO:93, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:1 12, SEQ ID NO:115, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:162, SEQ ID NO:163, SEQ IDNO:164, and SEQ ID NO:165.

[0036] Preferred peptides for antifungal applications include SEQ IDNO:2, SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ IDNO:16, SEQ ID NO:17, SEQ ID NO:25, SEQ ID NO:30, SEQ ID NO:35, SEQ IDNO:58, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:80, SEQ ID NO:81, SEQ IDNO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:106, SEQ ID NO:108, SEQ IDNO:115, SEQ ID NO:116, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:131, SEQID NO:143, SEQ ID NO:163, and SEQ ID NO:165.

[0037] An additional embodiment of the invention is the use of any ofthe above described peptides to inhibit or kill cancer cells. The methodgenerally is directed towards the contacting of cancer cells with thepeptide. The contacting step can be performed in vivo, in vitro,topically, orally, transdermally, systemically, or by any other methodknown to those of skill in the art. The contacting step is preferablyperformed at a concentration sufficient to inhibit or kill the cancercells. The concentration of the peptide can be at least about at leastabout 0.1 μM, at least about 0.5 M, at least about 1 μM, at least about10 μM, at least about 20 μM, at least about 50 μM, or at least about 100μM. The cancer cells can generally be any type of cancer cells. Thecancer cells can be sarcomas, lymphomas, carcinomas, leukemias, breastcancer cells, colon cancer cells, skin cancer cells, ovarian cancercells, cervical cancer cells, testicular cancer cells, lung cancercells, prostate cancer cells, and skin cancer cells. The contacting stepcan be performed by subcutaneous, IP injection, IM injection, IVinjection, direct tumor injection, or topical application. Forinjection, the dosage can be between any of the followingconcentrations: about 0.1 mg/kg, about 1 mg/kg , about 5 mg/kg, about 10mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, and about 100mg/kg. The contacting step can be performed on a mammal, a cat, a dog, acow, a horse, a pig, a bird, a chicken, a plant, a fish, a goat, asheep, or a human. The inhibition of cancer cells can generally be anyinhibition of growth of the cancer cells as compared to the cancer cellswithout peptide treatment. The inhibition is preferably at least about10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,and ideally 100% inhibition of growth. The inhibition may be achieved bylysis of the cancer cells or by other means. The cancer inhibitingpeptide can be used synergistically with other cancer chemotherapeuticagents.

[0038] Preferred peptides for anticancer applications include SEQ IDNO:1, SEQ ID NO:2, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:13, SEQ IDNO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ IDNO:25, SEQ ID NO:26, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ IDNO:35, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:56, SEQ ID NO:57, SEQ IDNO:58, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:75, SEQ ID NO:86, SEQ IDNO:152, and SEQ ID NO:162

[0039] An additional embodiment of the invention is directed towards amethod for promoting the stimulation and/or proliferation of cells. Themethod can comprise contacting the cells and a composition, wherein thecomposition comprises a peptide. The peptide can be any of the abovedescribed peptides. The concentration of the peptide in the compositioncan be about 0.01 μM to about 500 μM, about 0.1 μM to about 100 μM,about 1 μM to about 50 μM, or about 1 μM to about 10 μM. The cells cangenerally be any type of cells, and preferably are mammalian cells,specifically including, but not limited to fibroblast and leukocytecells, including lymphocyte and phagocytic cells. The metabolicstimulation and/or proliferation of the cells is preferably increased byat least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%,150%, 175%, or 200% relative to the same cells not contacted with thecomposition. The composition can further comprise a growth factor. Thestimulatory and proliferative properties of some of the FLAK peptideshold promise for their application in skin care, wound healing, and inimmunomodulation of compromised mammalian immune systems.

[0040] Preferred peptides for stimulation and proliferation applicationsinclude SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8,SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:27, SEQ IDNO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:45, SEQ IDNO:46, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:55, SEQ ID NO:56, SEQ IDNO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ IDNO:65, SEQ ID NO:66, SEQ ID NO:71, SEQ ID NO:74, SEQ ID NO:75, SEQ IDNO:77, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:87, SEQ ID NO:90, SEQ IDNO:91, SEQ ID NO:92, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:126, SEQ IDNO:127, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:137, SEQ ID NO:138, SEQID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143,SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:159, SEQ ID NO:162, and SEQ IDNO:164.

[0041] An additional embodiment of the invention is directed towards amethod for promoting wound healing of skin or ocular and internal bodytissues damaged by normal aging, disease, injury, or by surgery or othermedical procedures. The method can comprise administering to the woundof an animal a composition, wherein the composition comprises any of theabove described peptides. The concentration of the peptide in thecomposition can be about 0.01 μM to about 500 μM, about 0.1 μM to about100 μM, about 1 μM to about 50 μM, or about 1 μM to about 10 μM. Thecomposition can be administered to the wound topically or by systemicdelivery. The animal can generally be any kind of animal, preferably isa mammal, and more preferably is a human, cow, horse, cat, dog, pig,goat, or sheep. The promotion of wound healing is preferably at least10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or200% relative to the same wound not contacted with the composition.

[0042] Preferred peptides for wound healing applications include SEQ IDNO:1, SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10,SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15,SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:27, SEQ ID NO:28,SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:45, SEQ ID NO:46,SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57,SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:65,SEQ ID NO:66, SEQ ID NO:71, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:77,SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:87, SEQ ID NO:90, SEQ ID NO:91,SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:126,SEQ ID NO:127, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:137, SEQ IDNO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:159, SEQ ID NO:162,and SEQ ID NO:164.

[0043] A further embodiment of the invention is directed towards methodsfor the additive or synergistic enhancement of the activity of atherapeutic agent. The method can comprise preparing a composition,wherein the composition comprises a peptide and a therapeutic agent.Alternatively, the method may comprise co-therapy treatment with apeptide (or peptides) used in conjunction with other therapeutic agents.The peptide can be any of the above described peptides. The therapeuticagent can generally be any therapeutic agent, and preferably is anantibiotic, an antimicrobial agent, a growth factor, a chemotherapyagent, an antimicrobial agent, lysozyme, a chelating agent, or EDTA.Preferably, the activity of the composition is higher than the activityof the same composition containing the therapeutic agent but lacking thepeptide. The composition or co-therapy can be used in in vitro, in vivo,topical, oral, IV, IM, IP, and transdermal applications. The enhancementof the activity of the composition containing the therapeutic agent andthe peptide is preferably at least 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, 125%, 150%, 175%, or 200% relative to the activity ofthe therapeutic agent alone.

[0044] Generally, any peptide which is active on a stand-alone basisagainst a target is preferred for use to increase either additively orsynergistically the activity of another therapeutic agent against thattarget. If several peptides are candidates for a given synergyapplication, then the less toxic peptides would be more favorablyconsidered.

[0045] The following Examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLES Example 1: Antimicrobial assays

[0046] The data for the antimicrobial assay of the peptides have beenobtained by making OD measurements in in vitro cell culture experimentswith and without added peptide. The protocol used is as follows.

[0047] Cell lines included Staphylococcus aureus ATCC 6538 or 25923,Pseudomonas aeruginosa ATCC 9027 or 29853. Medium used were AntibioticMedium 3 (Difco), Antibiotic Medium 2 (Difco), and 0.85% saline.Controls used were physiological saline, and gentamycin at 50, 25, 10,5, 1, and 0.1 ppm.

[0048] The preparation of all media, stock solutions, and dilutions tookplace in a laminar flow hood to prevent contamination. Bacterial cellswere freshly grown on antibiotic medium 2 agar slants (pH 7.0 at 25°C.). Bacteria were suspended and diluted in antibiotic medium 3 to about10⁴ cfu/ml and used as the inoculum. Sample solutions (100 μl/well) wereadded to plates according to the plate layout. Inoculum (100 μl/well)was added to achieve a final concentration of 5×10³ cfu/ml. Negativecontrols received 100 μl saline and 100 μl growth medium. Positivecontrols received 100 μl saline and 100 μl inoculum. Bacterial plateswere incubated at 37° C. for 24 hours.

[0049] Absorbance was read at 620 nm after shaking to resuspend cells.The minimum inhibitory concentration (MIC) was defined as the lowestconcentration of peptide that completely inhibits the growth of the testorganism.

[0050] The yeast assay was performed in RPMI 1640 media (pH 7.0 at 25°C).

[0051] The data presented in Table 2 were obtained using the aboveprotocol. However, the data for Table 3 were obtained with a modifiedprotocol wherein the medium was tryptic soy broth, inocolum strength wasapproximately 10⁴ CFU per ml, and values determined were minimumbactericidal concentrations (MBC) or minimum fungicidal concentrations(MFC).

[0052] The following Table 2 describes the antimicrobial properties ofthe peptides measured as MIC or MFC values in μg/mL. Staph6538 isStaphylococcus aureus ATCC accession number 6538; paerug9027 isPseudomonas aeruginosa ATCC accession number 9027, yeast isSaccharomyces cerevisiae. TABLE 2 SEQ ID Name NO: P Number staph6538paerug9027 yeast Hecate AC #1010 1 1 5 10 > Hecate AM 2 2 25 100 25SB-37 AC #1018 3 5 100 50 > SB-37 AM 5 12 > 100 > Shiva 10 AC 6 1310 > > #1015 FLAK01 AM 8 23 5 50 100 FLAK04 AM 10 25 10 5 25 FLAK05 AM11 26 10 15 > FLAK06 AM 12 27 10 10 25 KAL V 15 30 > > ND FLAK 17 AM 1634 5 50 25 FLAK 26 AM 17 35 5 200 25 Hecate 2DAc 19 37 5 100 50 FLAK43AM 20 38 5 50 50 FLAK44 AM 21 39 100 25 100 FLAK62 AM 22 40 100 25 100FLAK 06R-AM 23 41 10 10 ND MSI-78 AM 24 42 10 > 200 FLAK50 25 43 5 10025 FLAK51 26 44 5 5 50 FLAK57 27 45 5 100 100 FLAK71 28 46 10 5 50FLAK77 29 47 200 100 50 FLAK50V 30 48 5 5 25 FLAK50F 31 49 10 200 50FLAK26V AM 32 50 5 15 50 CAME-15 33 53 5 15 50 FLAK50C 34 54 5 50 50FLAK50D 35 55 5 5 25 FLAK 50E 36 56 200 5 50 FLAK80 37 57 100 200 200FLAK81 38 58 100 100 200 FLAK82 39 59 > > > FLAK83M 40 60 200 100 200FLAK 17 C 43 64 5 > 200 FLAK 50H 44 65 15 50 200 FLAK 50G 45 66 5 50 100Shiva deriv 46 70 10 > 100 P69 + KWKL Shiva 10 (1-18_(—) 47 71 15 15 200AC CA(1-7) 49 73 50 15 100 Shiva10(1-16) FLAK 54 50 74 15 5 100 FLAK 5651 75 5 5 50 FLAK 58 52 76 10 100 200 FLAK 72 53 77 200 100 200 FLAK 7554 79 100 200 100 Shiva 10 55 80 10 100 100 (1-16) Ac CA(1-7)Shiva10 5681 10 > > (1-16)-COOH Indolocidin-ac 57 91 10 > > FLAK50B 58 92 5 5 50FLAK50I 60 94 10 > > FLAK50K 61 95 100 200 > FLAK50L 62 96 > > >Shiva-11 63 98 > > > Shiva 11[(1- 64 99 100 > > 16)ME(2-9)]- COOH FLAK50N 65 101 10 25 100 FLAK 50O 66 102 5 10 50 FLAK 50P 67 103 10 25 100CA(1- 68 104 10 10 200 &Hecate(11/23) PYL-ME 69 105 200 200 > FLAG26-D170 106 100 25 100 Vishnu3 71 107 > > > Melittin 72 108 5 > 25 FLAK26-D273 109 > 200 200 FLAG26-D3 74 110 > 200 200 FLAK50 Q1 75 111 5 100 200FLAK50 Q2 76 112 50 200 100 FLAK50 Q3 77 113 10 200 200 FLAK50 Q4 78 11450 15 100 FLAK50 Q5 79 117 100 200 200 FLAK50 Q6 80 118 10 100 100FLAK50 Q7 81 119 50 25 50 FLAK50 Q8 82 120 50 200 200 FLAK50 Q9 83 12150 > 100 FLAK50 T1 85 123 50 200 100 FLAK50 T2 86 124 5 100 100 FLAK50T3 87 125 10 100 50 FLAK50 T4 88 126 > > > FLAK50 T5 89 127 100 25 100FLAK90 90 128 > 100 200 FLAK91 91 129 100 25 100 FLAK92 92 130 200 200200 FLAK93 93 131 25 10 100 FLAK50 Z1 94 132 > 100 > FLAK50 Z2 95133 > > > FLAK50 Z3 96 134 100 > 200 FLAK50 Z4 97 135 15 10 50 FLAK50 Z598 136 100 50 100 FLAK50 Z6 99 137 > > > FLAK50 Z7 100 138 > > > FLAK50Z8 101 139 50 25 200 FLAK50 Z9 102 140 > > > FLAK94 103 141 15 50 200FLAK93B 104 142 100 50 100 FLAK50 Z10 105 143 100 50 200 FLAK96 106 1445 50 50 FLAK97 107 145 200 100 200 FLAK98 108 146 10 10 50 FKRLA 109 1475 5 200 FLAK91B 110 148 > 200 200 FLAK92B 111 149 50 100 200 FLAK99 112150 100 10 > FLAK50T6 113 151 > > 200 FLAK50T7 114 152 100 50 100 FLAK95115 153 5 25 100 FLAK50T8 116 154 100 100 50 FLAK50T9 117 155 > > >FLAK100-CO2H 118 156 15 > > FAGVL 119 157 200 > > FLAK120 126 165 10 2525 FLAK121 127 166 > > > FLAK96B 128 167 10 25 100 FLAK96G 129 168 50100 > FLAK96F 130 169 100 100 100 FLAK96C 131 170 200 100 100 FLAK96D132 171 25 50 100 FLAK 96 137 176 > > > FLAK 96J 139 178 200 100 > FLAK96L 140 179 50 50 100 FLAK-120G 141 180 200 > > FLAK-120D 142 181 100200 100 FLAK-120C 143 182 > > > FLAK-120B 144 183 200 100 200 FLAK-120F145 184 25 100 100 FLAK 50M 165 97 5 50 50

[0053] The following Table 3 describes describes the antimicrobialproperties of the peptides measured as minimum bactericidal or minimumfungicidal (Candida) concentrations. MBC or MFC values are in μg/mL. E.coli is Escherichia coli ATCC number 25922; P. aerug is Pseudomonasaeruginosa ATCC accession number 27853, S. aur. is Stapholococcus aureusATCC accession number 25923; Candida is Candidia albicans ATCC accessionnumber 10231. TABLE 3 E. coli P. aerug S. aur Candida SEQ ID NO: P #A.25922 A.27853 A.25923 A.10231 1  1 25 30 25 >50 2  2 25 10 25 >50 3  550 >60 40 ND 4  11 40 25 25 >50 5  12 50 >60 75 ND 6  13 8 15 30 >50 8 23 15 25 30 >50 9  24 >80 30 >40 >50 10  25 40 30 40 >50 11 26 >80 >40 >40 >50 12  27 10 8 8 >50 13   27B 40 10 >40 >40 14   27C 104 >40 >40 15  30 10 15 40 >50 16  34 15 15 40 >40 17  35 8 8 10 >40 18 36 30 15 10 >40 19  37 8 8 40 >50 20  38 15 30 15 ND 21  39 >40 >40 >40ND 22  40 30 40 >40 ND 23  41 40 40 40 ND 24  42 10 30 10 ND 25  43 8 154 15 26  44 10 55 30 >50 27  45 30 40 80 >50 29  47 >50 >50 >50 >50 30 48 8 25 4 10 31  49 40 30 50 30 32  50 50 25 25 >50 33  53 15 15 10 3034  54 15 40 15 30 35  55 4 10 4 25 36  56 50 10 55 30 37 57 >50 >50 >50 >50 38  58 >50 >50 >50 >50 39  59 >50 >50 >50 >50 40 60 >50 >50 >50 >50 41  61 4 50 >80 >40 42  63 10 50 15 60 43  64 10 304 >50 44  65 >55 >50 >55 >50 45  66 40 50 30 40 46  70 40 30 40 >50 47 71 50 40 >50 >50 48  72 >50 40 >50 >50 50  74 >55 50 >55 >55 51  75 4030 >55 30 52  76 40 >55 >55 >50 53  77 >50 >50 >50 >50 54 79 >50 >50 >50 >50 55  80 30 15 >50 >50 58  92 40 25 15 25 59 93 >50 >50 >50 >50 60  94 >50 >50 >50 >50 61  95 >50 >50 >50 >50 62 96 >50 >50 >50 >50 65 101 300 >50 >50 40 66 102 25 30 25 15 67 103 3030 >50 25 69 105 25 >50 ND >50 70 106 50 >50 ND >50 71 107ND >50 >50 >50 72 108 >50 >50 25 >50 73 109 ND ND 80 >50 74 1108 >50 >50 >50 75 111 30 ND 40 INACT 76 112 30 INACT INACT INACT 77 113INACT INACT INACT 40 79 117 INACT INACT INACT INACT 80 118 8 25 10 25 81119 15 30 4 25 82 120 INACT INACT INACT INACT 83 121 INACT INACT INACT50 84 122 30 30 25 15 85 123 40 INACT INACT 25 86 124 10 40 8 15 87 12540 40 INACT 40 88 126 INACT INACT INACT INACT 89 127 INACT INACT INACTINACT 90 128 INACT INACT INACT INACT 91 129 INACT INACT INACT INACT 92130 INACT INACT INACT INACT 93 131 INACT INACT INACT INACT 94 132 INACTINACT INACT INACT 95 133 INACT INACT INACT INACT 96 134 INACT INACTINACT INACT 97 135 INACT 40 INACT 25 98 136 INACT INACT INACT INACT 99137 INACT INACT INACT INACT 100 138 INACT INACT INACT INACT 101 139INACT INACT INACT INACT 102 140 INACT INACT INACT INACT 103 141 INACTINACT INACT INACT 104 142 INACT INACT INACT INACT 105 143 INACT INACTINACT INACT 106 144 10 25 25 25 107 145 INACT INACT INACT 100 108 14610 >250 75 10 109 147 25 75 >250 >250 110 148 150 >250 >250 100 111 149150 >250 >250 100 112 150 75 >250 >250 50 113 151 >250 >250 >250 100 114152 150 150 >250 50 115 153 10 25 5 25 116 154 50 100 >250 25 117155 >250 >250 >250 >250 118 156 100 >250 >250 >250 119 15775 >250 >250 >250 120 159 10 10 >250 50 121 160 >250 >250 >250 >250 122161 150 >250 >250 25 123 162 50 >250 >250 100 124 163 25 50 25 25 125164 25 25 25 25 126 165 10 25 25 10 127 166 >250 >250 >250 >250 128 16725 >250 10 25 129 168 75 100 >250 150 130 169 200 >250 >250 75 131 17025 >250 150 25 132 171 75 100 >250 50 133 172 >250 >250 >250 >250 134173 >250 >250 >250 150 162  67 25 30 30 >50 165  97 25 >50 25 25

Example 2: Anti-cancer assays

[0054] Cancer cell assays were performed in a manner similar to theanti-microbial assays above, except that the assay procedure used theMTT dye protocol. Viability of determined by the dye response. In thefollowing procedure, approximately 1.5×10⁴ cells per well were added andviability was determined with the cells in a semi-confluent state. Theassay was performed in a 96-well microtiter plate. After addition ofpeptide, the plate was set for 24 hours. MTT (5 mg/ml in phenol red-freeRPMI-1640, 20 μl) was added to each well including positive controlwells untreated with peptide. The plate was incubated at 37° C. for 4hours. The liquid contents of each well was removed, and isopropanolwith 0.1 M HCl (100 μl ) was added to each well. The plate was sealedwith parafilm to prevent evaporation of the isopropanol. The plate isallowed to rest for 5-10 minutes in order to solubilize the precipitate.Purified water (100 μl) was added to each well. Aborbance was determinedwith an ELISA Reader instrument. Color intensity at 540 nm proportionalto viability of cells. Results for each concentration of peptide areplotted relative to untreated controls, and LD50 values are determinedfrom the graphs.

[0055] W138 (ATCC No. CCL75) is a normal fibroblast line of lung diploidcells, MCF7 (ATCC No. HTB22) is a breast adenocarcinoma tumor cell line,SW480 (ATCC No. CCL228) is a colon adenocarcinoma tumor cell line, BMKCis a cloned melanoma line derived from Bowes melanoma line HMCB (ATCCNo. CRL9607), H1299 (ATCC No. CRL5803) is a lung large cell carcinomatumor line, HeLaS3 (ATCC No. CCL2.2) is a cervical epitheleal carcinomatumor cell line, and PC3 (ATCC No. CRL1435) is a prostate adenocarcinomatumor cell line. Numbers are LD₅₀ values (μg/mL). Data on the sixtargets are presented in the following Tables 4 and 5. TABLE 4 SEQ ID PName NO: No. WI38 MCF7 SW480 BMKC HECATE AC 1  1 27 54 6 72 HECATE AM 2 2 66 23 46 128 SB37COOH 3  5 130 175 82 120 SB-37 AM 5  12 950 540 > >SHIVA 10 AC 6  13 57 > ND ND FLAK01 AM 8  23 34 62 5 27 FLAK03 AM 9  2455 26 38 85 FLAK04 AM 10  25 24 10 12 36 FLAK05 AM 11  26 96 74 8 94FLAK06 AM 12  27 37 14 26 44 FLAK06 AC 13   27B 101 65 59 93 FLAK06 R-AC14   27C 520 140 210 300 KAL V 15  30 93 72 62 140 FLAK 17 AM 16  34 4021 35 53 FLAK 26 AM 17  35 8 9 14 7 FLAK 25 AM 18  36 19 9 30 56 HECATE2DAc 19  37 80 14 57 150 FLAK43 AM 20  38 12 17 13 21 FLAK44 AM 21  39300 130 435 510 FLAK62 AM 22  40 > 760 > > FLAK 06R-AM 23  41 175 98 120290 MSI-78 AM 24  42 67 31 34 140 FLAK50 25  43 5 9 9 7 FLAK51 26  44 36140 32 47 FLAK57 27  45 200 260 180 160 FLAK71 28  46 200 300 160 150FLAK77 29  47 > 575 > 700 FLAK50V 30  48 41 23 47 43 FLAK50F 31  49 13540 100 115 FLAK26V AM 32  50 43 32 46 40 CAME-15 33  53 32 45 40 FLAK50C34  54 97 60 90 FLAK50D 35  55 32 16 14 16 FLAK 50E 36  56 250 500 215205 FLAK80 37  57 900 > 740 740 FLAK81 38  58 > > > > FLAK82 39  59 7731 42 155 FLAK83M 40  60 > > > > FLAK 26 Ac 41  61 93 105 100 140INDOLICIDIN 42  63 ND 64 345 200 FLAK 17 C 43  64 37 80 35 FLAK 50H 44 65 320 475 345 250 FLAK 50G 45  66 240 90 145 200 SHIV A DERIV 46  7034 44 11 94 P69 + KWKL SHIVA 10 47  71 355 190 250 445 (1-18_AC SHIVA 1048  72 125 93 82 290 PEPTIDE 71 + KWKL CA(1-7) 49  73 160 150 70 360Shiva10(1-16) FLAK 54 50  74 335 465 340 460 FLAK 56 51  75 80 42 17 24FLAK 58 52  76 445 970 400 750 FLAK 72 53  77 > > > 125 FLAK 75 54  79 >540 > 830 SHIVA 10 55  80 28 29 35 76 (1-16) Ac CA(1-7) 56  81 8 63 1312 Shiva10(1-16)- COOH INDOLOCIDIN-ac 57  91 9 12 30 180 FLAK50B 58  9243 23 51 46 FLAK50I 60  94 6 65 ND 11 FLAK50K 61  95 250 > > 820 FLAK50L62  96 > > > > Shiva-11 63  98 47 96 125 94 SHIVA 11 64  99 34 95 120 94[(1-16) ME(2-9]- COOH FLAK 50N 65 101 300 250 170 160 FLAK 50O 66 102 7360 57 60 FLAK 50P 67 103 26 46 90 75 CA(1- 68 104 24 11 54 100&HECATE(11/23) PYL-ME 69 105 430 635 > ND FLAG26-D1 70 106 > 620 570 690VISHNU3 71 107 > > > > MELITTIIN 72 108 16 9 23 18 FLAK26-D2 73109 > > > > FLAG26-D3 74 110 45 180 325 400 FLAK50 Q1 75 111 24 35 27 26FLAK50 Q2 76 112 420 500 800 445 FLAK50 Q3 77 113 170 150 180 115 FLAK50Q4 78 114 > 730 > > FLAK50 Q5 79 117 > > > > FLAK50 Q6 80 118 170 70 115135 FLAK50 Q7 81 119 45 54 46 36 FLAK50 Q8 82 120 600 730 630 660 FLAK50Q9 83 121 625 400 800 670 FLAK50 Q10 84 122 720 360 570 700 FLAK50 T1 85123 600 615 > 635 FLAK50 T2 86 124 21 18 9 10 FLAK50 T3 87 125 90 90 125220 FLAK50 T4 88 126 > > > > FLAK50 T5 89 127 760 440 400 535 FLAK90 90128 500 500 530 330 FLAK91 91 129 > > 550 > FLAK92 92 130 > > > > FLAK9393 131 > 600 555 > FLAK50 Z1 94 132 > > > > FLAK50 Z2 95 133 > > > >FLAK50 Z3 96 134 > > 740 > FLAK50 Z4 97 135 110 54 80 155 FLAK50 Z5 98136 > 500 600 530 FLAK50 Z6 99 137 > > > > FLAK50 Z7 100 138 > > > >FLAK50 Z8 101 139 550 625 > 525 FLAK50 Z9 102 140 > > > > FLAK94 103 141420 430 560 465 FLAK93B 104 142 73 44 38 38 FLAK50 Z10 105 143 > > > >FLAK96 106 144 750 150 285 250 FLAK97 107 145 > > > > FLAK98 108 146 270110 380 185 FKRLA 109 147 83 106 185 110 FLAK91B 110 148 380 315 > 330FLAK92B 111 149 > > > > FLAK99 112 150 125 160 235 190 FLAK50T6 113151 > > > > FLAK50T7 114 152 620 430 740 > FLAK95 115 153 130 64 61 165FLAK50T8 116 154 600 315 750 330 FLAK50T9 117 155 > > > > FLAK100-CO2H118 156 230 135 345 520 FAGVL 119 157 500 240 530 600 Modelin-5 120 15982 61 140 140 Modelin-5-CO2H 121 160 700 320 370 220 FLAK120 126 165 470360 240 240 FLAK121 127 166 > > > > FLAK96B 128 167 260 230 360 240FLAK96G 129 168 > 630 > 590 FLAK96F 130 169 > 510 > 530 FLAK96C 131170 > 940 > > FLAK96D 132 171 615 305 770 600 Modelin-8D 135 174 > > > >Modelin-8E 136 175 > > 70 > Flak 96H 137 176 > > > > Flak 96I 138 177270 190 310 310 Flak 96J 139 178 405 770 > 640 Flak 96L 140 179 540555 > 920 FLAK-120G 141 180 940 950 600 770 FLAK-120D 142 181 500 550870 830 FLAK-120C 143 182 > > > > FLAK-120B 144 183 > > > > FLAK-120F145 184 800 260 440 600 Magainin2wisc 146 300 52 22 60 130 D2A21 147 30166 64 76 140 KSL-1 148 302 800 340 > 700 KSL-7 149 303 355 315 530 330LSB-37 150 306 320 50 240 170 Anubis-2 151 307 75 38 73 83 FLAK 17 CV152 501 26 23 ND ND FLAK50 Q1V 153 502 64 92 ND ND D2A21V 154 503 150210 ND ND FLAK 25 AM V 155 504 110 130 ND ND FLAK43 AM V 156 505 85 86ND ND FLAK50D V 157 506 75 45 ND ND HECATE AM V 158 507 285 340 ND NDHECATE AC V 159 508 190 160 ND ND FLAK04 AM V 160 509 95 84 ND ND 03 AMV 161 510 77 62 ND ND 162  67 4 7 ND ND 163 100 95 175 82 120 164  69101 45 63 66

[0056] TABLE 5 SEQ ID P Name NO: No. WI38 H1299 HeLaS3 PC3 HECATE AC 1 1 27 44 95 61 HECATE AM 2  2 66 140 50 44 SB37COOH 3  5 130 220 150 NDSB-37 AM 5  12 950 720 > 630 SHIVA 10 AC 6  13 57 > > 83 FLAK01 AM 8  2334 64 82 41 FLAK03 AM 9  24 55 72 145 38 FLAK04 AM 10  25 24 37 20 12FLAK05 AM 11  26 96 84 150 125 FLAK06 AM 12  27 37 16 25 8 FLAK06 AC 13  27B 101 54 80 16 FLAK06 AM 14   27C 520 170 260 280 KAL V 15  30 93125 190 65 FLAK 17 AM 16  34 40 24 62 9 FLAK 26 AM 17  35 8 16 27 5 FLAK25 AM 18  36 19 57 ND 19 HECATE 2DAc 19  37 80 150 ND 64 FLAK43 AM 20 38 12 33 35 10 FLAK44 AM 21  39 300 420 620 310 FLAK62 AM 22  40 > > >435 FLAK 06R-AM 23  41 175 245 185 140 MSI-78 AM 24  42 67 150 ND 66FLAK50 25  43 5 6 15 12 FLAK51 26  44 36 72 22 45 FLAK57 27  45 200 330160 170 FLAK71 28  46 200 290 280 280 FLAK77 29  47 > > > > FLAK50V 30 48 41 17 44 32 FLAK50F 31  49 135 140 ND 77 FLAK26V AM 32  50 43 7 3354 CAME-15 33  53 32 65 30 40 FLAK50C 34  54 97 80 190 90 FLAK50D 35  5532 7 15 47 FLAK 50E 36  56 250 370 300 435 FLAK80 37  57 900 > 830 >FLAK81 38  58 > > > > FLAK82 39  59 77 180 ND 81 FLAK83M 40  60 > > > >FLAK 26 Ac 41  61 93 127 170 66 INDOLICIDIN 42  63 ND 270 345 290 FLAK17 C 43  64 37 30 30 46 FLAK 50H 44  65 320 450 210 470 FLAK 50G 45  66240 130 140 170 SHIVA DERIV 46  70 34 63 28 82 P69 + KWKL SHIVA 10 47 71 355 320 570 270 (1-18_AC SHIVA 10 48  72 125 160 240 63 PEPTIDE 71 +KWKL CA(1-7) 49  73 160 115 270 97 Shiva10(1-16) FLAK 54 50  74 335 670260 660 FLAK 56 51  75 80 80 74 54 FLAK 58 52  76 445 860 380 675 FLAK72 53  77 > > > > FLAK 75 54  79 > > > > SHIVA 10 55  80 28 64 97 28(1-16) Ac CA(1-7) 56  81 8 22 19 170 Shiva10(1-16)- COOH Indolocidin-ac57  91 9 64 20 31 FLAK50B 58  92 43 25 670 83 FLAK50J 59  93 530 320 >690 FLAK50I 60  94 6 ND > ND FLAK50K 61  95 250 > > > FLAK50L 62 96 > > > > Shiva-11 63  98 47 53 175 52 SHIVA 11 64  99 34 54 180 28[(1-16) ME(2-9]- COOH FLAK 50N 65 101 300 340 170 730 FLAK 50O 66 102 7327 43 66 FLAK 50P 67 103 26 150 70 330 CA(1- 68 104 24 52 130 18&HECATE(11/23) PYL-ME 69 105 430 > > ND FLAG26-D1 70 106 > 920 700 >VISHNU3 71 107 > > > > MELITTIIN 72 108 16 25 35 13 FLAK26-D2 73109 > > > > FLAG26-D3 74 110 45 95 540 > FLAK50 Q1 75 111 24 8 7 11FLAK50 Q2 76 112 420 470 660 640 FLAK50 Q3 77 113 170 50 190 240 FLAK50Q4 78 114 > > > > FLAK50 Q5 79 117 > > > > FLAK50 Q6 80 118 170 74 87330 FLAK50 Q7 81 119 45 33 30 140 FLAK50 Q8 82 120 600 620 810 > FLAK50Q9 83 121 625 460 830 > FLAK50 Q10 84 122 720 830 780 800 FLAK50 T1 85123 600 > 940 > FLAK50 T2 86 124 21 30 14 10 FLAK50 T3 87 125 90 76 220145 FLAK50 T4 88 126 > > > > FLAK50 T5 89 127 760 770 610 > FLAK90 90128 500 > 700 > FLAK91 91 129 > 790 550 > FLAK92 92 130 > > > > FLAK9393 131 > > > > FLAK50 Z1 94 132 > > > > FLAK50 Z2 95 133 > > > > FLAK50Z3 96 134 > > > > FLAK50 Z4 97 135 110 115 215 310 FLAK50 Z5 98 136 >450 400 900 FLAK50 Z6 99 137 > > > > FLAK50 Z7 100 138 > > > > FLAK50 Z8101 139 550 850 > > FLAK50 Z9 102 140 > > 285 > FLAK94 103 141 420 > >ND FLAK93B 104 142 73 115 55 60 FLAK50 Z10 105 143 > > > > FLAK96 106144 750 225 275 350 FLAK97 107 145 > > 240 > FLAK98 108 146 270 93 640440 FKRLA 109 147 83 93 > 340 FLAK91B 110 148 380 660 > > FLAK92B 111149 > > > > FLAK99 112 150 125 185 320 74 FLAK50T6 113 151 > > > >FLAK50T7 114 152 620 410 > > FLAK95 115 153 130 50 140 97 FLAK50T8 116154 600 400 > 640 FLAK50T9 117 155 > > > ND FLAK100-CO2H 118 156 230ND > 260 FAGVL 119 157 500 315 > 375 Modelin-5 120 159 82 74 275 145Modelin-5-CO2H 121 160 700 470 550 450 FLAK120 126 165 470 56 400 340FLAK121 127 166 > > > > FLAK96B 128 167 260 300 325 320 FLAK96G 129168 > > > > FLAK96F 130 169 > 640 > > FLAK96C 131 170 > > > > FLAK96D132 171 615 540 820 600 Modelin-8D 135 174 > > > > Modelin-8E 136175 > > 510 > Flak 96H 137 176 > > > > Flak 96I 138 177 270 240 380 120Flak 96J 139 178 405 > > > Flak 96L 140 179 540 > > > FLAK-120G 141 180940 > 760 > FLAK-120D 142 181 500 > > > FLAK-120C 143 182 > > > >FLAK-120B 144 183 > > > > FLAK-120F 145 184 800 370 302 570Magainin2wisc 146 300 52 60 125 45 D2A21 147 301 66 77 170 45 KSL-1 148302 800 720 > > KSL-7 149 303 355 345 > 530 LSB-37 150 306 320 120 250370 Anubis-2 151 307 75 160 100 66 163 100 95 220 150 ND 164  69 101 71190 81

[0057] It can be seen from Tables 4 and 5 that all targets challengedwere inhibited by one or more of the peptides to an appreciable extent(i.e. LD50 less than 50 μg/ml). Table 6 below shows that 44 (29%) of the150 peptides tested were active with some LD50 values at or below 50; 26of the peptides were active on some targets at or below the LD50 valueof 25; and 16 peptides were very active on one or more target strainswith LD50 values at or below 10.

[0058] Table 7 below shows a broad spectrum of activity against sixcancer cell types for various active peptides. It is noted that eachtarget has one or more lead candidate peptides inhibitory to cell growthat an LD50 level of 10 or less. TABLE 6 FLAK peptides showingsubstantial activity against cancer cell lines Percent of 150 LD50values Number of “active” peptides peptides tested < or = 50 μg/ml 4429% < or = 25 μg/ml 26 17% < or = 10 μg/ml 16 11%

[0059] TABLE 7 Activity and specificity of FLAK peptides against sixcancer cell targets Number of active peptides per target MCF7 SW480 BMKCH1299 HeLaS3 PC3 LD50 (breast) (colon) (melanoma) (lung) (cervix)(prostate) < or = 50 μg/ml 31 25 19 19 17 20 < or = 25 μg/ml 17 13 8 108 11 < or = 10 μg/ml 6 5 3 4 1 5

Example 3: Stimulation and proliferation of leukocytes

[0060] In vitro viability of human leukocyte cells in the presence ofdifferent peptides at different concentrations was determined by anAlamar Blue protocol. Alamar Blue (Promega, Madison, Wis.) is anindicator dye, formulated to measure quantitatively the proliferationand cytotoxicity of the cells. The dye consists of anoxidation-reduction (redox) indicator that yields a calorimetric changeand a fluorescent signal in response to cellular metabolic activity.

[0061] Assay protocol: Blood from a 50 year old male human was drawn andcentrifuged at 1500 rpm for 15 minutes at room temperature. The buffycoat cells at the plasma-red blood cell interface were aspirated. Buffycoat cells (mainly lymphocyte cells) were then transferred into 15 mlcentrifuge tubes containing 5 ml of RPMI-1640 medium+10% is Fetal BovineSerum (Gibco, Grand Island, N.Y.). Additional medium was added to thetubes to bring the volume up to 10 ml. The buffy coat suspension wasthen carefully layered on 5 ml of Histopaque (Sigma Chemical Co., St.Louis, Mo.) and centrifuged at 1500 rpm for 30 minutes at roomtemperature. The interface which is mostly PBMCs (peripheral mononuclearcells) was aspirated and transferred to a 15 ml conical centrifuge tubeand, resuspended in 2 ml cold RPMI-1640 and brought up to 15 ml withcold RPMI-1640 medium. Cells were centrifuged at 1500 rpm for 10minutes. The supernatant was then aspirated and discarded. The cellpellet was re-suspended in 1 ml of cold RPMI 1640 and brought up to 15ml with RPMI medium. This step was repeated twice, except that in thelast step, the cells were resuspended with 1 ml of cold RPMI-1640 mediumand cell counts were performed with a hemocytometer according to theSigma cell culture catalogue.

[0062] Pokewood mitogen was used as a control along with positive andnegative controls. Negative control cells were killed with 70% methanol.Positive (+) control cells were incubated in RPMI medium (untreated). 20ml of AlamarBlue was added to the cells, and readings were taken after24 hours, 48 hours, 72 hours, and 96 hours using a fluorimeter(excitation 544/transmission 590 nm).

[0063] Calculations were performed using the following formula:${\% \quad {treated}\quad {cell}\quad {viability}} = {\frac{{Peptide}\quad {treated}\quad {sample}\quad \left( {{{adj}.\quad {for}}\quad {negative}\quad {control}} \right)}{{Positive}\quad {control}\quad \left( {{{adj}.\quad {for}}\quad {negative}\quad {control}} \right)} \times 100\%}$

[0064] Using the protocol described immediately above, about 100-150peptides were screened for their stimulatory and/or inhibitory actionsupon the growth of human leukocyte (“WBC”) cells as compared to thegrowth of untreated positive control cells. The data in Table 8 belowshow that various selected FLAK peptides are stimulatory at lowconcentrations (0.1 to 1.0 μg/ml), whereas certain of the peptidesbecome inhibitory (causing cell death) at higher concentrations. Severalof the peptides (i.e. SEQ ID NOS: 5, 143, and 160) are stimulatory(and/or proliferative) at all concentrations through 500 μg/ml.

[0065] The Alamar Blue stain used in the protocol permeates both celland nuclear membranes, and is metabolized in the mitochondria to causethe change in color. The resulting fluorometric response is therefore aresult of total mitochondrial activity caused by cell stimulation and/ormitosis (cell proliferation). The increase in values (for treated cells,as a percent of values for untreated cells) with increased incubationtime (120 hours vs. 48 hours) may be attributed to increased cellproliferation in addition to stimulation of cell metabolic activitycaused by the peptide

[0066] Table 8 presents viability data, as percent of untreated positivecontrol, for human leukocytes (white blood cells, “WBC”) in the presenceof selected FLAK peptides. The table also shows for each of thesepeptides its toxicity (LD50 values) to human red blood cells (RBC) andto human fibroblast cells (WI38). Those certain peptides which arestimulatory to WBCs at low peptide concentrations (i.e. 10 μg/ml orless) and are inhibitory or toxic to WBCs at higher concentrations arealso relatively more toxic to RBCs and to fibroblasts than thosepeptides which are stimulatory and not inhibitory to WBC growth even atconcentrations as high as 500 μg/ml.

[0067] In limited experiments with other than the Alamar Blue protocoldescribed above, it has been qualitatively determined that thosepeptides which cause stimulation and proliferation of leukocytes areactive upon both the phagocytic and lyphocyte cell components of themammalian lymphatic system. As such, certain of the stimulatory FLAKpeptides which are relatively non-toxic to mammalian cells attherapeutic dose levels may be used as immunomodulators to treat humansor other mammals with compromised immune systems. Such treatment may beadministered systemically in vivo or by extra-corporeal treatment ofwhole blood or blood components to be reinfused to the donor. Suchtherapy would serve to counteract immune deficiency in neutropenicpatients caused by age, disease, or chemotherapy and would stimulatenatural immune responses to prevent or combat pathogenic infections andgrowth of certain cancer cell lines or to enhance wound healingprocesses involving the lymphoid system. Table 9 is a more detailedexample (with one peptide, SEQ ID NO:10) of the phenomenon showing therelationships of concentration and time as they effect stimulation,proliferation, and inhibition of the leukocytes. TABLE 8 Human leukocyte(WBC) stimulation/proliferation & inhibition by selected FLAK peptides0.1 Peptide 0.1 μg/ml 1 μg/ml 10 μg/ml SEQ ID conc. μg/ml 120 1 μg/ml120 10 μg/ml 120 NO: P Number 48 hours hours 48 hours hours 48 hourshours 5 12 111 124 115 136 118 141 10 25 117 135 104 118 99 119 12 27108 117 110 126 99 114 17 35 115 113 119 105 114 81 20 38 115 110 119117 114 109 25 43 115 100 119 114 114 104 58 92 112 120 112 114 98 99 66102 100 89 102 90 97 110 143 182 101 134 96 117 101 133 150 306 97 94101 113 94 109 100 500 Peptide 100 μg/ml 500 μg/ml RBC WI-38 SEQ IDconc. μg/ml 120 μg/ml 120 toxicity toxicity NO: P Number 48 hours hours48 hours hours LD50 LD50 5 12 116 151 101 119 >1000 950 10 25 27 43 2745 60 24 12 27 30 43 23 39 125 37 17 35 73 42 72 43 200 8 20 38 73 60 7257 350 12 25 43 73 39 72 37 20 5 58 92 35 30 26 26 300 125 66 102 37 3217 15 300 73 143 182 109 150 105 132 >1000 660 150 306 109 140 112140 >1000 320

[0068] TABLE 9 Human leukocyte (WBC) stimulation/proliferation andinhibition by FLAK peptide SEQ ID NO: 10 (P25) Time of 0.1 1 10 100 500incubation μg/ml μg/ml μg/ml μg/ml μg/ml 24 hours 111 98 88 10 10 48hours 117 104 99 27 27 72 hours 119 105 102 31 32 96 hours 128 112 11038 40 120 hours  135 118 119 43 45

Example 4: Stimulation and proliferation of fibroblasts

[0069] The cyQUANT cell proliferation assay provides a convenient, rapidand sensitive procedure for determining the density of cells in culture.The assay has a linear detection range extending from 50 or fewer to atleast 50,000 cells in 200 μl volumes using a single dye concentration.The assay is ideal for cell proliferation studies as well as for routinecell counts and can be used to monitor the adherence of cells tosurfaces.

[0070] Procedure: Different cell lines were maintained with differentmedium according to the ATCC. Cells were trypsinized with 8 ml ofTrypsin (0.25%, Fisher, Pittsburgh, Pa.). The cell suspension wascentrifuged for 10 minutes at 100 rpm. The supernatant was removed anddiscarded without disturbing the cell pellet. A concentrated cellsuspension was prepared in 1.0 ml of medium to obtain a density of about10⁵ to 10⁶ cells/ml. The actual cell density was determined by countingthe cells using a hemocytometer with the Trypan Blue method. Cellnumbers were adjusted to obtain equal number of cells per 200 gl volume.Cells were plated with 0% FBS, 2.5% FBS, 5% FBS and 10% FBS. The plateswere incubated at 37° C. for a time sufficient to allow the cells toattach. For long-term proliferation studies, 100 gl of medium wasremoved from each well each day and replaced with fresh medium.

[0071] At the desired time, the medium was removed from the adherentcells in a 96 well plate. These cells were already treated with testagents. The cells were frozen in the plate at −70° C. for 30 minutes.The cells were thawed at room temperature. CyQuant GR dry/Cell LysisBuffer (200 μl) was added to each sample cell. The cells were incubatedat room temperature for 15 minutes while protected from the light.Fluorescence was measured using fmax at 485-538 nm.

[0072] The above CyQuant protocol was used to examine possible peptidestimulation of fibroblasts. In the following Table 10, data are shownfor selected peptides demonstrating their effect on human fibroblastcells (WI38). In the table, the substantial stimulatory and/orproliferative property of selected peptides, as a function ofconcentration is evident. The values are viability of treated cellsexpressed as percent (%) above or below positive control (untreatedcells). Table 11 shows that the fibroblast stimulation and/orproliferation effect is enhanced for certain peptides in the presence ofother growth factors. This is shown by the addition of Fetal BovineSerum (FBS) to the medium. Negative values indicate inhibitory action ofthe peptide, especially at concentrations above 10 μg/ml. TABLE 10 Humanfibroblast (WI-38) cell stimulation by selected FLAK peptides Peptideconcentration SEQ ID P % FBS in 0.1 1 10 100 NO: Number serum μg/mlμg/ml μg/ml μg/ml 2  2 0 −27 −3 27 −82 2.5 26 57 23 −66 4 11 0 19 34 50−40 2.5 50 52 62 14 6 13 0 76 68 93 95 8 23 0 21 78 10 −48 2.5 16 23 5875 10 25 0 50 59 29 −27 14   27C 0 60 85 90 63 15 30 0 60 75 20 35 17 350 45 70 65 50 20 38 0 44 22 75 53 35 55 0 1 12 30 76 5 12 0 (24 h inc)93 90 116 65 58 92 0 (24 h inc) 109 114 132 36 71 107  0 18 27 26 24 80118  0 12 −4 −7 −1 0 (24 h inc) 24 55 48 24 3 61 70 68 72 126 165  0 5177 115 50

[0073] TABLE 11 Effect of growth factors on human fibroblast (WI38) cellstimulation Peptide concentration SEQ ID P % FBS in 0.1 1 10 100 NO:Number serum μg/ml μg/ml μg/ml μg/ml 2 2 0 −27 −3 27 −82 2.5 26 57 23−66 4 11 0 19 34 50 −40 2.5 50 52 62 14 8 23 0 21 78 10 −48 2.5 16 23 5875 80 118 0 12 −4 −7 −1 3 61 70 68 72

Example 5: Toxicitv assay—Red blood cell (RBC) hemolysis, and leukocyte(WBC) and fibroblast (WI38) inhibition

[0074] Table 12 below summarizes the RBC, WBC, and W138 toxicity datafor typical FLAK peptides. The three RBC, WBC, and W138 values (LD50)are generally consistent directional indicators of peptide toxicity. Inchoosing a peptide for possible treatment of a given indication it isimportant to match the therapeutic activity and specificity of thepeptide with its possible toxic properties. The SEQ ID NO:5 peptide isnot a FLAK peptide, but rather it is SB-37, a close homolog of CecropinB. It has previously been shown not to be as active as the FLAK peptidesas an antibacterial agent, but to possess wound healing properties asdemonstrated in vivo in a rat model. This probably results from itsstimulatory and proliferative effects on both mammalian leukocytes andfibroblasts.

[0075] The protocols for WBC and WI38 stimulation have been discussedabove. The RBC protocol follows Table 12. TABLE 12 In vitro toxicity ofselected FLAK peptides on red blood cells (RBC), human leukocytes (WBC),and human fibroblasts (WI38) RBC LD50 WBC LD50 WI38 LD50 SEQ ID NO: PNumber μg/ml μg/ml μg/ml 5 12 >1000 >500 60 10 25 60 79 60 11 26 900 185100 12 27 125 78 60 16 34 200 77 200 17 35 200 64 25 20 38 350 160 10025 43 20 70 25 30 48 130 78 70 35 55 30 80 28 58 92 300 51 400 66 102300 115 45

[0076] The RBC protocol is as follows. Well positions of each dilutionand untreated controls are recorded on the lid of a 96-well plate. Whenthe cells were confluent, the media is removed, and replaced withfreshly prepared sample dilutions to a final volume of 200 μl. Testagent was added into designed wells of the 96-well plate. The 200 μlfresh medium was added to positive control wells; and 200 μl of 70%ethanol was added to negative control wells. The plate was incubatedovernight at 37° C., 5% CO₂, and at least 90% humidity. Room temperatureAlamarBlue solution (20 μl) was added to all wells. The plates were readspectrofluorometrically (excitation 544 nm, emission 590 nm). The plateswere incubated for 3 hours at 37° C., 5% CO₂, and at least 90% humidity.The plates were read again at 3 and 24 hours incubation. The LD50endpoint was determined from the graph by reading from where the 50percent point intercepts the Dose Response Curve to the concentrationalong the x-axis. That concentration is the LD50 value. The LD50 valuefor test agents within a single test agent class can be used torank-order their relative toxicities or to correlate with in vivo data.

[0077] This hemolytic assay is based upon that presented in JournalofPeptide Research 53: 82-90 (1999). Preparation of all media, stocksolutions and dilutions were performed in a laminar flow hood tominimize or prevent contamination. All procedures were performedaccording to safety protocols pertaining to the handling and disposal ofhuman body fluids.

[0078] Red blood cells (RBCs) were washed three times with PBS (35 mMphosphate buffer 0.15 M NaCl, pH 7.0). RBCs suspended in PBS (0.4%(v/v); about 10 ml per 15 peptides) were prepared. Suspensions (100 μl)were aliquoted to each sample and control tube. Serially diluted peptidesolutions (100 μl) were pipetted into the sample tubes. Negative controltubes contained 100 μl PBS; positive control tubes contained 100 μl 1%Triton-X100 detergent. All tubes were incubated for 1 hour at 37° C. Thetubes were removed from the incubator and centrifuged at 1000 g for 5minutes. Supernatant (100 μl) was pipetted to a 96-well polyvinylchloride plate. The absorbance at 414 nm (A₄₁₄) was measured, and usedto calculate the percent hemolysis according to the following formula.$\frac{\left( {{A_{414}\quad {in}\quad {peptide}\quad {solution}} - {A_{414}\quad {in}\quad {PBS}}} \right)}{\left( {{A_{414}\quad {in}\quad {Triton}\text{-}X\quad 100} - {A_{414}\quad {in}\quad {PBS}}} \right)} \times 100\%$

[0079] Percent hemolysis is plotted against peptide concentration, andthe concentration at which 50% hemolysis is determined (LD₅₀). Thefollowing Table 13 details the results of the hemolytic assay using thepeptides discussed herein. TABLE 13 Peptide name SEQ ID NO: P NumberLD₅₀ μg/mL Hecate AC #1010 1  1 100 Hecate AM 2  2 10 SB-37 AC #1018 3 5 > Shiva 10 AM 4  11 76 SB-37 AM 5  12 > Shiva 10 AC #1015 6  13 50Magainin 2 7  16 550 FLAK01 AM 8  23 300 FLAK03 AM 9  24 10 FLAK04 AM 10 25 16 FLAK05 AM 11  26 90 FLAK06 AM 12  27 125 FLAK06 AC 13   27B 700FLAK06 R-AC 14   27C 250 KALV 15  30 150 FLAK 17 AM 16  34 200 FLAK 26AM 17  35 200 FLAK 25 AM 18  36 85 Hecate 2DAc 19  37 30 FLAK43 AM 20 38 350 FLAK44 AM 21  39 > FLAK62 AM 22  40 > FLAK 06R-AM 23  41 40MSI-78 AM 24  42 300 FLAK50 25  43 20 FLAK51 26  44 90 FLAK57 27  45 700FLAK71 28  46 900 FLAK77 29  47 > FLAK50V 30  48 200 FLAK50F 31  49 225FLAK26V AM 32  50 420 CAME-15 33  53 20 FLAK50C 34  54 250 FLAK50D 35 55 20 FLAK 50E 36  56 600 FLAK80 37  57 > FLAK81 38  58 > FLAK82 39  591000 FLAK83M 40  60 > FLAK 26 Ac 41  61 390 Indolicidin 42  63 375 FLAK17 C 43  64 6 FLAK 50H 44  65 950 FLAK 50G 45  66 600 Shiva deriv P69 +KWKL 46  70 80 Shiva 10 (1-18_ AC 47  71 > Shiva 10 peptide 48  72 11071 + KWKL CA(1-7)Shiva10 49  73 90 (1-16) FLAK 54 50  74 > FLAK 56 51 75 750 FLAK 58 52  76 > FLAK 72 53  77 > FLAK 75 54  79 > Shiva 10(1-16) Ac 55  80 900 CA(1-7)Shiva10 56  81 8 (1-16)-COOH Indolocidin-ac57  91 40 FLAK50B 58  92 300 FLAK50J 59  93 > FLAK50I 60  94 350 FLAK50K61  95 > FLAK50L 62  96 > Shiva-11 63  98 60 Shiva 11[(1-16)ME 64  99 25(2-9)]-COOH FLAK 50N 65 101 550 FLAK 50O 66 102 500 FLAK 50P 67 103 650CA(1-&Hecate(11/23) 68 104 70 PYL-ME 69 105 ND FLAG26-D1 70 106 >Vishnu3 71 107 > Melittin 72 108 <1 FLAK26-D2 73 109 > FLAG26-D3 74110 > FLAK50 Q1 75 111 60 FLAK50 Q2 76 112 > FLAK50 Q3 77 113 1000FLAK50 Q4 78 114 > FLAK50 Q5 79 117 > FLAK50 Q6 80 118 700 FLAK50 Q7 81119 400 FLAK50 Q8 82 120 > FLAK50 Q9 83 121 > FLAK50 Q10 84 122 > FLAK50T1 85 123 1000 FLAK50 T2 86 124 55 FLAK50 T3 87 125 > FLAK50 T4 88 126 >FLAK50 T5 89 127 > FLAK90 90 128 > FLAK91 91 129 > FLAK92 92 130 >FLAK93 93 131 > FLAK50 Z1 94 132 > FLAK50 Z2 95 133 > FLAK50 Z3 96 134 >FLAK50 Z4 97 135 900 FLAK50 Z5 98 136 > FLAK50 Z6 99 137 > FLAK50 Z7 100138 20 FLAK50 Z8 101 139 > FLAK50 Z9 102 140 > FLAK94 103 141 900FLAK93B 104 142 900 FLAK50 Z10 105 143 > FLAK96 106 144 600 FLAK97 107145 > FLAK98 108 146 180 FKRLA 109 147 300 FLAK91B 110 148 > FLAK92B 111149 > FLAK99 112 150 650 FLAK50T6 113 151 > FLAK50T7 114 152 880 FLAK95115 153 800 FLAK50T8 116 154 450 FLAK50T9 117 155 > FLAK100-CO2H 118 15610 FAGVL 119 157 850 Modelin-5 120 159 ND Modelin-5-CO2H 121 160 >FLAK120 126 165 350 FLAK121 127 166 > FLAK96B 128 167 200 FLAK96G 129168 600 FLAK96F 130 169 > FLAK96C 131 170 > FLAK96D 132 171 550Modelin-8D 135 174 > Modelin-8E 136 175 > Flak 96 137 176 > Flak 96I 138177 400 Flak 96J 139 178 > Flak 96L 140 179 850 FLAK-120G 141 180 >FLAK-120D 142 181 > FLAK-120C 143 182 > FLAK-120B 144 183 > FLAK-120F145 184 850 Magainin2wisc 146 300 250 D2A21 147 301 10 KSL-1 148 302 >KSL-7 149 303 500 LSB-37 150 306 > Anubis-2 151 307 > FLAK17CV 152 50115 FLAK50Q1V 153 502 100 D2A21V 154 503 20 FLAK25AMV 155 504 70FLAK43AMV 156 505 620 FLAK50DV 157 506 120 HECATE AMV 158 507 20 HECATEACV 159 508 70 FLAK04AMV 160 509 40 FLAK03AMV 161 510 10 D-Shiva 10 AC162  67 40 Shiva 11 AC 163 100 > Shiva 10 (1-18)AM 164  69 900

Example 6: Effects of valine substitution

[0080] Changing a peptide sequence where the first amino acid is valine,and particularly when the first amino acid is changed from phenylalanineto valine, can lead to desirable properties. The red blood cell andfibroblast cell (WI38) toxicity can be decreased, while notsignificantly decreasing other desirable properties. Table 14 belowshows numerous examples (14) of reducing the indicated toxicity of apeptide as seen from increase in viabiltiy of both red blood cells andfibroblast cells when treated with peptide. LD50 values are in μg/ml.TABLE 14 Hemo- SEQ. lysis ID P RBC WI-38 NO: No. Sequence LD50 LD50 2 2FALALKALKKALKKLKKALKKAL-NH2 12 66 15 30 VALALKALKKALKKLKKALKKAL-NH2 15093 17 35 FAKKLAKLAKKLAKLAL-NH2 150 25 32 50 VAKKLAKLAKKLAKLAL-NH2 420 4525 43 FAKLLAKLAKKLL-NH2 20 25 30 48 VAKLLAKLAKKLL-NH2 130 160 86 124FAKLLAKLAKKVL-NH2 55 21 116 154 VAKLLAKLAKKVL-NH2 870 110 126 165FALALKALKKL-NH2 350 850 141 180 VALALKALKKL-NH2 850 1000 43 64FAKALKALLKALKAL-NH2 6 37 152 501 VAKALKALLKALKAL-NH2 15 26 75 111FAKFLAKFLKKAL-NH2 5 25 153 502 VAKFLAKFLKKAL-NH2 100 64 47 301FAKKFAKKFKKFAKKFAKFAFAF-NH2 10 66 154 503 VAKKFAKKFKKFAKKFAKFAFAF-NH2 20150 18 36 FAKKLAKLAKKLAKLALAL-NH2 12 19 155 504 VAKKLAKLAKKLAKLALAL-NH270 110 20 38 FAKKLAKLAKKLLAL-NH2 350 100 156 505 VAKKLAKLAKKLLAL-NH2 62085 35 55 FAKLLAKALKKLL-NH2 20 32 157 506 VAKLLAKALKKLL-NH2 120 75 1 1FALALKALKKALKKLKKALKKAL-COOH 20 27 159 508 VALALKALKKALKKLKKALKKAL-COOH70 190 10 25 FALALKALKKLAKKLKKLAKKAL-NH2 16 24 160 509VALALKALKKLAKKLKKLAKKAL-NH2 40 95 9 24 FALALKALKKLLKKLKKLAKKAL-NH2 10 55161 510 VALALKALKKLLKKLKKLAKKAL-NH2 10 77

[0081] Although the effects of reduction of toxicity to mammalian cellsby valine substitution is accompanied by modest reductions oftherapeutic activity against microbial pathogens and cancer cells, thereare some cases in which the valine substitution results in a desirableincrease in therapeutic activity. This can be seen in the followingTable 15 where it is shown that the valine substitution in some caseshas increased the peptide's activity against the gram negative bacteriumPseudomonas.

[0082] Hemolysis and W138 values represent LD50 values. P. aerug valuesrepresent MIC values in μg/mL against Pseudomonas aeruginosa ATCCaccession number 9027. TABLE 15 SEQ ID P NO: No. Sequence Hemolysis WI38P. aerug 17 35 FAKKLAKLAKKLAKLAL 100 25 200 32 50 VAKKLAKLAKKLAKLAL 42045 15 25 43 FAKLLAKLAKKLL 20 25 100 30 48 VAKLLAKLAKKLL 200 160 5 86 124FAKLLAKLAKKVL 300 21 100 116 154 VAKLLAKLAKKVL 450 110 100

Example 7: Preferred peptides

[0083] Preferred peptides can be selected from the above describedexperimental data. Preferred antimicrobial peptides for gram positive orgram negative bacteria can be selected as having MIC values of less thanor equal to about 10 μg/ml, or as having MBC values of less than orequal to about 25 μg/ml. Preferred antifungal peptides can be selectedas having MIC or MBC values of less than or equal to about 25 μg/ml.Preferred anticancer peptides can be selected as having LD50 values ofless than or equal to about 25 μg/ml.

[0084] The following Table 16 lists representative preferred peptides,where an ‘X’ indicates the peptide is a preferred peptide for thatcolumn's property. The peptide's “length” is the number of amino acidresidues in the sequence. TABLE 16 SEQ ID P- Length Anti- Anti- Anti-NO: number (AA) bacterial fungal cancer 1  1 23 X X 2  2 23 X X X 4 1123 X 6 13 23 X 8 23 23 X X 10 25 23 X X 11 26 21 X X X 12 27 19 X X 13  27B 19 X X X 14   27C 19 X 15 30 23 X 16 34 16 X X X 17 35 17 X X X 1836 19 X X 19 37 23 X X 20 38 15 X X 23 41 19 X 25 43 13 X X X 26 44 15 XX 27 45 14 X 28 46 15 X 29 47 12 X 30 48 13 X X X 31 49 12 X 32 50 17 XX 34 54 13 X 35 55 13 X X X 36 56 13 X 41 61 15 X 43 64 15 X 45 66 13 X46 70 23 X X 50 74 13 X 51 75 13 X X 52 76 14 X 55 80 23 X 56 81 23 X X57 91 15 X X 58 92 13 X X X 60 94 13 X X 65 101  13 X 66 102  13 X X 67103  12 X X 68 104  20 X X 74 110  12 X 75 111  13 X X 77 113  13 X 80118  13 X X 81 119  14 X X 84 122  13 X X 85 123  10 X 86 124  13 X X X87 125  13 X 93 131  5 X 106 144  12 X X 108 146  13 X X 112 150  17 X115 153  17 X X 116 154  13 X 126 165  11 X X 128 167  12 X X 131 170 10 X 143 182  10 X 152 501  15 X 162 67 23 X X 163 100  13 X X 164 69 23X 165 97 13 X X

[0085] Preferred peptides for stimulation and proliferation can also beselected. The following Table 17 lists representative preferredpeptides, where an ‘X’ indicates that the peptide is a preferred peptidefor that column's property. Peptides which are stimulatory for leukytesat 0.1 μg/ml to 1.0 μg/ml concentration are preferred, as at thisconcentration the peptides are not toxic to red blood cells, WI-3 8fibroblasts, or to human leukocytes. Peptides which are stimulatory forfibroblasts at 0.1 μg/ml to 1.0 μg/ml are preferred, as at thisconcentration the peptides are not toxic. TABLE 17 Preferred peptidesfor leukocyte and fibroblast stimulation/proliferation SEQ ID NO:P-number Length Leukocyte Fibroblast 1 29 23 X X 2  2 23 X X 5 12 38 X X6 13 23 X X 8 23 23 X X 10 25 23 X X 11 26 21 X X 12 27 19 X X 13   27B19 X X 14   27C 19 X X 15 30 23 X X 16 34 16 X X 17 35 17 X X 20 38 15 X27 45 14 X 28 46 15 X 30 48 13 X 32 50 17 X 34 54 13 X 45 66 13 X X 4670 23 X X 50 74 13 X X 51 75 13 X X 55 80 23 X 56 81 23 X 57 91 15 X X58 92 13 X X 59 93 13 X 60 94 13 X 61 95 13 X X 65 101  13 X 66 102  13X 71 107  19 X X 74 110  12 X 75 111  13 X 77 113  13 X 80 118  13 X 81119  14 X 87 125  13 X X 90 128  5 X X 91 129  5 X 92 130  5 X 115 153 17 X 116 154  13 X 126 165  11 X 127 166  11 X 129 168  6 X X 132 171 11 X 137 176  11 X 138 177  12 X 139 178  11 X X 140 179  11 X X 141180  11 X X 142 181  10 X X 143 182  10 X X 144 183  5 X X 145 184  5 XX 159 508  23 X X 162 67 23 X X 164 69 18 X

Example 8: Synergistic effects with lysozyme

[0086] Synergy between lytic peptides and lysozyme was assayed.Sterilized milk was inoculated with bacteria to 5×10⁵ per ml. PeptideShiva-10 (SEQ ID NO:4) was added to 10 μg/ml, and chicken lysozyme wasadded to 1 mg/ml. The percent killing of bacteria was determined. TABLE18 Staph. aureus Pseud. aeruginosa Peptide and lysozyme 0% 100%  Peptide0% 0% Lysozyme 0% 0%

[0087] Synergy between cecropin SB-37 (SEQ ID NO:5) and lysozyme wasdetermined against Pseudomonas syringae pv. tabaci (PSPT), Pseudomonassolanacearum (PS), Erwinia caratovora subsp. carotova (EC), andXanthomonas campestris pv. campestris (XC). LD₅₀ (μM) values weredetermined. TABLE 19 SB-37 Lysozyme SB-37 and Lysozyme PSPT 5.20 > 0.19PS 64.0 > 16.0 EC 1.48 > 0.44 XC 0.57 > 0.027

[0088] Synergy between Shiva-1 and lysozyme was determined. The percentviability of Pseudomonas aeruginosa was determined relative to blankcontrols. Lysozyme was used at the same molar concentration as thepeptide. TABLE 20 Peptide concen- Shiva-1 and tration (μM) SB-37 Shiva-1Lysozyme (1x) Lysozyme (1x) 0 100 100 100 100 0.01 100 100 100 56.6 0.179.4 69.6 82.2 25.8 1 48.8 37.9 52.1 4.4 5 38.5 1.5 7.9 0.2 7.5 0.7 0.10.6 0 25 0 0 0.4 0

[0089] Synergy between Shiva-1 and lysozyme was determined. The percentviability of gram positive S. intermedius 19930, S. intermedius 20034,and S. aureus was determined relative to blank controls. Lysozyme wasused at ten times the molar concentration as the peptide. TABLE 21 S.intermedius 19930 Peptide con- Shiva-1 and centration (μM) SB-37 Shiva-1Lysozyme (10x) Lysozyme (10x) 0 100 100 100 100 0.01 100 100 100 100 0.194.7 81.8 100 79.2 0.5 69.4 65.0 81.3 65.1 1 42.5 42.1 53 43 5 36.1 35.249.5 17.2 10 5.6 1.2 34.4 1.1 50 0 0 22 0

[0090] TABLE 22 S. intermedius 20034 Peptide con- Shiva-1 and centration(μM) SB-37 Shiva-1 Lysozyme (10x) Lysozyme (10x) 0 100 100 100 100 0.01100 100 100 100 0.25 85.4 87.1 100 85.1 0.5 68.0 80.0 59.0 53.4 0.7562.2 60.1 42.3 41.0 5 35.1 4.1 38.3 4.3 50 0 0 10.0 0

[0091] TABLE 23 S. aureus Peptide con- Shiva-1 and centration (μM) SB-37Shiva-1 Lysozyme (10x) Lysozyme (10x) 0 100 100 100 100 0.01 100 100 100100 0.1 100 100 100 100 0.5 81.0 50.1 100 100 1 47.5 24.4 51.0 31.2 531.8 15.9 18.4 8.2 10 5.6 4.5 13.3 4.5 50 1.9 1.6 9.5 1.4

[0092] Synergy experiments can also be performed using peptides in thepresence of EDTA, which potentiates the peptides additively orsynergistically.

Example 9: Synergistic effects with antibiotics

[0093] Synergy between peptide Shiva-10 (SEQ ID NO:4) and variousantimicrobial agents was investigated against Escherichia coli 25922.The following table illustrates the beneficial effects of combining thepeptide with the agents, where the numbers are the minimum bactericidalconcentration (MBC; μg/mL). TABLE 24 Agent Without peptide With peptideShiva-10 50 n/a Ticarcillin 100 50 (15 μg/mL peptide) Cefoperazone 1502.5 (15 μg/mL peptide)  Doxycycline 5  1 (15 μg/mL peptide) Neomycin 1005 (5 μg/mL peptide) Amikacin 150 50 (5 μg/mL peptide)  Tetracycline 102.5 (5 μg/mL peptide)  

[0094] Synergy between peptide Shiva-10 (SEQ ID NO:4) and variousantimicrobial agents was investigated against Staph. aureus 29213. Thefollowing table illustrates the beneficial effects of combining thepeptide with the agents, where the numbers are the minimum bactericidalconcentration (MBC; μg/mL). TABLE 25 Agent Without peptide With 5 μg/mLpeptide Shiva-10 200 n/a Ampicillin 5 2.5 Ticarcillin 25 15 Cefoperazone10 2.5 Tobramycin 25 10 Tetracycline 10 1

[0095] Synergy between peptide FLAK 26AM (P35; SEQ ID NO:17) and variousantimicrobial agents was investigated against Staph. aureus 29213 MBC.The following table illustrates the beneficial effects of combining thepeptide with the agents, where the numbers are the minimum bactericidalconcentration (MBC; μg/mL). This experiment determined the peptide MBCin the absence of the antimicrobial agent, or in the presence of theindicated concentration of antimicrobial agent TABLE 26 Agent MBC ofpeptide FLAK 26AM alone 50 Vancomycin (1 ppm) 32 Cefoperazone (0.25 ppm)20

[0096] Synergy between doxacycline and various peptides was investigatedagainst P. aeruginosa 27853. The following table illustrates thebeneficial effects of combining doxacycline and the peptides, where thenumbers are the minimum bactericidal concentration (MBC; μg/mL). Whencombined with the peptides, the doxacycline was held at 10 ppmconcentration. TABLE 27 Agent Without doxacycline With doxacyclineDoxacycline n/a 100 SB-37 (P5; SEQ ID NO: 3) 200 30 FLAK 26AM (P35; SEQID 50 32 NO: 17)

[0097] Synergy between tetracycline and various peptides wasinvestigated against Escherichia coli 25922 MBC. The following tableillustrates the beneficial effects of combining tetracycline and thepeptides, where the numbers are the minimum bactericidal concentration(MBC; μg/mL). When combined with the peptides, the concentration oftetracycline was held at 1.5 ppm. TABLE 28 Agent Without tetracyclineWith tetracycline Tetracycline n/a 10 FLAK 06AM (P27; SEQ ID 75 25 NO:12) FLAK 26AM (P35; SEQ ID 50 20 NO: 17)

Example 10: Synergistic effects with chemotherapy agents

[0098] Other investigators have reported that lytic peptides which areinhibitory to cancer cells will act synergistically with conventionalcancer chemotherapy drugs. The FLAK peptides are no exception. Table 29below demonstrates for example that selected FLAK peptides aresynergistic with Tamoxifen in the inhibition of the MCF7 line of breastcancer cells. Table 30 lists other more active anti-cancer peptidecandidates for synergistic application with Tamoxifen or other cancertherapy drugs.

[0099] Tables 29 and 30 also show toxicity of the selected peptidesagainst RBCs, WBCs, and W138 cells. When used at very low non-toxiclevels selected anti-cancer peptides can synergistically potentiateother chemotherapy agents to permit their effective use at substantiallylower dose levels with consequently fewer side effects. TABLE 29 Synergyof FLAK peptides with tamoxifen on MCF7 cells Active agent LD50 on MCF7cells SEQ ID NO: MCF7 Peptide Tamox. Total conc. (P No.) Agent LD50μg/ml conc. μg/ml conc. μg/ml μg/ml Tamoxifen 20 0 20 20 164 (69)  Alone79 With Tamox. 2.5 4.6 7.1 145 (184) Alone 240 With Tamox. 10 4 14 121(160) Alone 240 With Tamox. 11 3.7 14.7 106 (144) Alone 310 With Tamox.35 7.7 42.7 SEQ ID NO: MCF7 LD50 RBC LD50 WI38 LD50 WBC LD50 (P No.)μg/ml μg/ml μg/ml μg/ml 164 (69) 79 900 60 140  145 (184) 240 850 1000410  121 (160) 240 >1000 700 900  106 (144) 310 600 740 320  17 (35) 9200 25 25  32 (50) 32 420 40 420  20 (38) 17 350 100 54

[0100] TABLE 30 Other highly active peptide candidates for synergisticanti-cancer applications SEQ ID NO: MCF7 LD50 RBC LD50 WI38 LD50 WBCLD50 (P No.) μg/ml μg/ml μg/ml μg/ml 17 (35) 9 200 25 25 32 (50) 32 42040 420 20 (38) 17 350 100 54

Example 11: Synergistic effects with growth factors

[0101] It has been shown above in Example 4 and Table 11 that certain ofthe FLAK peptides are synergistic with other mitogens or growth factorsin the stimulatory and/or proliferative properties of the peptides.

Example 12: Activity against drug resistant strains

[0102] Peptides were assayed for their activity against tobramycinsensitive and resistant strains. As shown in the following Table 31,peptides P56 (SEQ ID NO:36), P74 (SEQ ID NO:50), and P125 (SEQ ID NO:87)showed enhanced activity against tobramycin resistant (tr) PseudomonasATCC 13096 than against tobramycin sensitive (ts) Pseudomonas ATCC27853. The same three peptides showed enhanced activity against clinicaltobramycin resistant strain 960890198-3c (Table 31). TABLE 31 Peptide trPseudomonas 13096 ts Pseudomonas 27853 SEQ ID NO: 36 (P56) 16 125 SEQ IDNO: 50 (P74) 16 125 SEQ ID NO: 87 (P125) 4 31

[0103] TABLE 32 tr Pseudomonas Peptide 960890198-3c ts Pseudomonas 27853SEQ ID NO: 36 (P56) >50 125 SEQ ID NO: 50 (P74) 25 125 SEQ ID NO: 87(P92) 50 63

[0104] The inventive peptides can be used in compositions for topical orsystemic delivery in wound healing applications. The compositions can bea liquid, cream, paste, or other pharmaceutically acceptableformulation. The compositions may contain other biologically activeagents. The compositions may contain pharmaceutically acceptablecarriers.

[0105] Those peptides preferred for wound healing, shown in Table 33below, are peptides which were preferred for either, or or both,leukocyte or fibroblast stimulation. TABLE 33 Preferred peptides forwound healing SEQ ID NO: P No. 1  1 2  2 5 12 6 13 8 23 10 25 11 26 1227 13   27B 14   27C 15 30 16 34 17 35 20 38 27 45 28 46 30 48 32 50 3454 45 66 46 70 50 74 51 75 55 80 56 81 57 91 58 92 59 93 60 94 61 95 65101  66 102  71 107  74 110  75 111  77 113  80 118  81 119  87 125  90128  91 129  92 130  93 131  115 153  116 154  126 165  127 166  129168  132 171  137 176  138 177  139 178  140 179  141 180  142 181  143182  144 183  145 184  159 508  162 67 164 69

[0106] All of the compositions and/or methods disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the compositions and methods of thisinvention have been described in terms of preferred embodiments, it willbe apparent to those of skill in the art that variations may be appliedto the compositions and/or methods and in the steps or in the sequenceof steps of the methods described herein without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention.

1 165 1 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 1 Phe Ala Leu AlaLeu Lys Ala Leu Lys Lys Ala Leu Lys Lys Leu Lys 1 5 10 15 Lys Ala LeuLys Lys Ala Leu 20 2 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 2 PheAla Leu Ala Leu Lys Ala Leu Lys Lys Ala Leu Lys Lys Leu Lys 1 5 10 15Lys Ala Leu Lys Lys Ala Leu 20 3 38 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 3 Met Pro Lys Trp Lys Val Phe Lys Lys Ile Glu Lys Val Gly ArgAsn 1 5 10 15 Ile Arg Asn Gly Ile Val Lys Ala Gly Pro Ala Ile Ala ValLeu Gly 20 25 30 Glu Ala Lys Ala Leu Gly 35 4 23 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 4 Phe Ala Lys Lys Leu Ala Lys Lys Leu Lys Lys Leu AlaLys Lys Leu 1 5 10 15 Ala Lys Leu Ala Leu Ala Leu 20 5 38 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 5 Met Pro Lys Trp Lys Val Phe Lys Lys IleGlu Lys Val Gly Arg Asn 1 5 10 15 Ile Arg Asn Gly Ile Val Lys Ala GlyPro Ala Ile Ala Val Leu Gly 20 25 30 Glu Ala Lys Ala Leu Gly 35 6 23 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 6 Phe Ala Lys Lys Leu Ala Lys LysLeu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala Lys Leu Ala Leu Ala Leu 207 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 7 Gly Ile Gly Lys PheLeu His Ser Ala Lys Lys Phe Gly Lys Ala Phe 1 5 10 15 Val Gly Gly IleMet Asn Ser 20 8 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 8 Phe AlaLeu Ala Ala Lys Ala Leu Lys Lys Leu Ala Lys Lys Leu Lys 1 5 10 15 LysLeu Ala Lys Lys Ala Leu 20 9 23 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 9 Phe Ala Leu Ala Leu Lys Ala Leu Lys Lys Leu Leu Lys Lys LeuLys 1 5 10 15 Lys Leu Ala Lys Lys Ala Leu 20 10 23 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 10 Phe Ala Leu Ala Leu Lys Ala Leu Lys LysLeu Ala Lys Lys Leu Lys 1 5 10 15 Lys Leu Ala Lys Lys Ala Leu 20 11 21PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 11 Phe Ala Leu Ala Lys LeuAla Lys Lys Ala Lys Ala Lys Leu Lys Lys 1 5 10 15 Ala Leu Lys Ala Leu 2012 19 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 12 Phe Ala Leu Ala LeuLys Ala Leu Lys Lys Leu Lys Lys Ala Leu Lys 1 5 10 15 Lys Ala Leu 13 19PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 13 Phe Ala Leu Ala Leu LysAla Leu Lys Lys Leu Lys Lys Ala Leu Lys 1 5 10 15 Lys Ala Leu 14 19 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 14 Phe Ala Lys Lys Leu Ala LysLys Leu Lys Lys Leu Ala Lys Leu Ala 1 5 10 15 Leu Ala Leu 15 23 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 15 Val Ala Leu Ala Leu Lys AlaLeu Lys Lys Ala Leu Lys Lys Leu Lys 1 5 10 15 Lys Ala Leu Lys Lys AlaLeu 20 16 16 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 16 Phe Ala LeuAla Leu Lys Lys Ala Leu Lys Ala Leu Lys Lys Ala Leu 1 5 10 15 17 17 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 17 Phe Ala Lys Lys Leu Ala LysLeu Ala Lys Lys Leu Ala Lys Leu Ala 1 5 10 15 Leu 18 19 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 18 Phe Ala Lys Lys Leu Ala Lys Leu Ala LysLys Leu Ala Lys Leu Ala 1 5 10 15 Leu Ala Leu 19 23 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 19 Phe Ala Leu Ala Leu Lys Ala Leu Lys LysAla Leu Xaa Xaa Leu Lys 1 5 10 15 Lys Ala Leu Lys Lys Ala Leu 20 20 15PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 20 Phe Ala Lys Lys Leu AlaLys Leu Ala Lys Lys Leu Leu Ala Leu 1 5 10 15 21 15 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 21 Phe Ala Lys Lys Leu Ala Lys Leu Ala LysLys Ala Leu Ala Leu 1 5 10 15 22 15 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 22 Phe Ala Leu Ala Lys Lys Ala Leu Lys Lys Ala Lys Lys Ala Leu1 5 10 15 23 19 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 23 Phe AlaLys Lys Leu Ala Lys Lys Leu Lys Lys Leu Ala Lys Leu Ala 1 5 10 15 LeuAla Lys 24 22 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 24 Gly Ile GlyLys Phe Leu Lys Lys Ala Lys Lys Phe Gly Lys Ala Phe 1 5 10 15 Val LysIle Leu Lys Lys 20 25 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 25Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys Leu Leu 1 5 10 26 15 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 26 Phe Ala Lys Lys Leu Ala LysLeu Ala Leu Lys Leu Ala Lys Leu 1 5 10 15 27 14 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 27 Phe Ala Lys Lys Leu Ala Lys Lys Leu Ala Lys LeuAla Leu 1 5 10 28 15 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 28 PheAla Lys Lys Leu Lys Lys Leu Ala Lys Leu Ala Lys Lys Leu 1 5 10 15 29 12PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 29 Phe Ala Lys Lys Ala LeuLys Ala Leu Lys Lys Leu 1 5 10 30 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 30 Val Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys Leu Leu 1 5 1031 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 31 Phe Ala Lys Leu LeuAla Lys Leu Ala Lys Lys Leu 1 5 10 32 17 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 32 Val Ala Lys Lys Leu Ala Lys Leu Ala Lys Lys LeuAla Lys Leu Ala 1 5 10 15 Leu 33 15 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 33 Lys Trp Lys Leu Phe Lys Lys Ile Gly Ala Val Leu Lys Val Leu1 5 10 15 34 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 34 Phe AlaLys Leu Leu Ala Lys Leu Ala Lys Lys Ala Leu 1 5 10 35 13 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 35 Phe Ala Lys Leu Leu Ala Lys Ala Leu LysLys Leu Leu 1 5 10 36 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 36Phe Ala Lys Leu Leu Lys Leu Ala Ala Lys Lys Leu Leu 1 5 10 37 10 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 37 Phe Ala Lys Leu Leu Ala LysLys Leu Leu 1 5 10 38 10 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 38Phe Ala Lys Lys Leu Ala Lys Ala Leu Leu 1 5 10 39 10 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 39 Phe Ala Lys Lys Leu Ala Lys Lys Leu Leu 15 10 40 9 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 40 Phe Ala Lys LeuAla Lys Lys Leu Leu 1 5 41 17 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE41 Phe Ala Lys Lys Leu Ala Lys Leu Ala Lys Lys Leu Ala Lys Leu Ala 1 510 15 Leu 42 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 42 Ile LeuPro Trp Lys Trp Pro Trp Trp Pro Trp Arg Arg 1 5 10 43 15 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 43 Phe Ala Lys Ala Leu Lys Ala Leu Leu LysAla Leu Lys Ala Leu 1 5 10 15 44 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 44 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Ala Lys Leu 1 5 1045 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 45 Phe Ala Lys Leu LeuAla Lys Leu Ala Lys Leu Lys Leu 1 5 10 46 22 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 46 Phe Ala Lys Lys Leu Ala Lys Lys Leu Lys Lys LeuAla Lys Lys Leu 1 5 10 15 Ala Lys Lys Trp Lys Leu 20 47 18 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 47 Phe Ala Lys Lys Leu Ala LysLys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala Lys 48 22 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 48 Phe Ala Lys Lys Leu Ala LysLys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala Lys Lys Trp Lys Leu 2049 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 49 Lys Trp Lys Leu PheLys Lys Lys Thr Lys Leu Phe Lys Lys Phe Ala 1 5 10 15 Lys Lys Leu AlaLys Lys Leu 20 50 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 50 PheAla Lys Lys Leu Ala Lys Lys Leu Ala Lys Ala Leu 1 5 10 51 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 51 Phe Ala Lys Lys Leu Ala LysLys Leu Ala Lys Leu Leu 1 5 10 52 14 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 52 Phe Ala Lys Lys Leu Ala Lys Lys Leu Ala Lys Ala Ala Leu 1 510 53 15 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 53 Phe Ala Lys LysLeu Ala Lys Lys Ala Lys Leu Ala Lys Lys Leu 1 5 10 15 54 12 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 54 Phe Ala Lys Lys Leu Lys LysLeu Ala Lys Lys Leu 1 5 10 55 23 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 55 Lys Thr Lys Leu Phe Lys Lys Phe Ala Lys Lys Leu Ala Lys LysLeu 1 5 10 15 Lys Lys Leu Ala Lys Lys Leu 20 56 23 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 56 Lys Trp Lys Leu Phe Lys Lys Lys Thr LysLeu Phe Lys Lys Phe Ala 1 5 10 15 Lys Lys Leu Ala Lys Lys Leu 20 57 13PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 57 Ile Leu Pro Trp Lys TrpPro Trp Trp Pro Trp Arg Arg 1 5 10 58 13 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 58 Phe Ala Lys Ala Leu Ala Lys Leu Ala Lys Lys LeuLeu 1 5 10 59 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 59 Phe AlaLys Leu Leu Ala Lys Leu Ala Lys Lys Ala Ala 1 5 10 60 13 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 60 Phe Ala Lys Leu Leu Ala Leu Ala Leu LysLeu Lys Leu 1 5 10 61 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 61Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Ala Lys Ala 1 5 10 62 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 62 Phe Ala Lys Leu Leu Ala LysLeu Ala Lys Ala Lys Gly 1 5 10 63 31 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 63 Phe Ala Lys Lys Leu Ala Lys Lys Leu Lys Lys Leu Ala Lys LysLeu 1 5 10 15 Ala Lys Leu Ala Leu Ala Leu Lys Ala Leu Ala Leu Lys AlaLeu 20 25 30 64 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 64 Phe AlaLys Lys Leu Ala Lys Lys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 IleGly Ala Val Leu Lys Val 20 65 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 65 Phe Ala Lys Leu Leu Ala Lys Ala Leu Lys Leu Lys Leu 1 5 1066 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 66 Phe Ala Lys Leu LeuAla Lys Ala Leu Lys Lys Ala Leu 1 5 10 67 12 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 67 Phe Ala Lys Leu Leu Ala Lys Ala Leu Lys Lys Leu 15 10 68 20 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 68 Lys Trp Lys LeuPhe Lys Lys Ala Leu Lys Lys Leu Lys Lys Ala Leu 1 5 10 15 Lys Lys AlaLeu 20 69 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 69 Lys Ile AlaLys Val Ala Leu Ala Lys Leu Gly Ile Gly Ala Val Leu 1 5 10 15 Lys ValLeu Thr Thr Gly Leu 20 70 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE70 Phe Ala Lys Lys Leu Ala Lys Leu Ala Lys Lys Leu 1 5 10 71 19 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 71 Met Pro Lys Glu Lys Val PheLeu Lys Ile Glu Lys Met Gly Arg Asn 1 5 10 15 Ile Arg Asn 72 26 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 72 Gly Ile Gly Ala Val Leu LysVal Leu Thr Thr Gly Leu Pro Ala Leu 1 5 10 15 Ile Ser Trp Ile Lys ArgLys Arg Gln Gln 20 25 73 16 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE73 Phe Ala Lys Lys Leu Ala Lys Leu Ala Lys Lys Leu Ala Lys Ala Leu 1 510 15 74 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 74 Phe Ala LysLys Leu Leu Ala Lys Ala Leu Lys Leu 1 5 10 75 13 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 75 Phe Ala Lys Phe Leu Ala Lys Phe Leu Lys Lys AlaLeu 1 5 10 76 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 76 Phe AlaLys Leu Leu Phe Lys Ala Leu Lys Lys Ala Leu 1 5 10 77 13 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 77 Phe Ala Lys Leu Leu Ala Lys Phe Leu LysLys Ala Leu 1 5 10 78 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 78Phe Ala Lys Leu Leu Ala Lys Ala Phe Lys Lys Ala Leu 1 5 10 79 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 79 Phe Ala Lys Leu Phe Ala LysAla Phe Lys Lys Ala Leu 1 5 10 80 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 80 Phe Ala Lys Leu Leu Ala Lys Ala Leu Lys Lys Phe Leu 1 5 1081 14 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 81 Phe Ala Lys Leu LeuAla Lys Ala Leu Lys Lys Phe Ala Leu 1 5 10 82 14 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 82 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys PheAla Leu 1 5 10 83 14 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 83 PheAla Lys Leu Phe Ala Lys Leu Ala Lys Lys Phe Ala Leu 1 5 10 84 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 84 Phe Lys Leu Ala Phe Lys LeuAla Lys Lys Ala Phe Leu 1 5 10 85 10 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 85 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys 1 5 10 86 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 86 Phe Ala Lys Leu Leu Ala LysLeu Ala Lys Lys Val Leu 1 5 10 87 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 87 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys Ile Leu 1 5 1088 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 88 Phe Ala Lys Leu LeuAla Lys Leu Ala Lys Lys Glu Leu 1 5 10 89 13 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 89 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys SerLeu 1 5 10 90 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 90 Phe AlaLys Leu Ala 1 5 91 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 91 PheAla Lys Leu Phe 1 5 92 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 92Lys Ala Lys Leu Phe 1 5 93 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE93 Lys Trp Lys Leu Phe 1 5 94 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 94 Phe Gly Lys Gly Ile Gly Lys Val Gly Lys Lys Leu Leu 1 5 1095 15 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 95 Phe Ala Phe Gly LysGly Ile Gly Lys Val Gly Lys Lys Leu Leu 1 5 10 15 96 22 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 96 Phe Ala Lys Ala Ile Ala Lys Ile Ala PheGly Lys Gly Ile Gly Lys 1 5 10 15 Val Gly Lys Lys Leu Leu 20 97 22 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 97 Phe Ala Lys Leu Trp Ala LysLeu Ala Phe Gly Lys Gly Ile Gly Lys 1 5 10 15 Val Gly Lys Lys Leu Leu 2098 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 98 Phe Ala Lys Leu TrpAla Lys Leu Ala Lys Lys Leu 1 5 10 99 13 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 99 Phe Ala Lys Gly Val Gly Lys Val Gly Lys Lys AlaLeu 1 5 10 100 15 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 100 Phe AlaPhe Gly Lys Gly Ile Gly Lys Ile Gly Lys Lys Gly Leu 1 5 10 15 101 16 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 101 Phe Ala Lys Ile Ile Ala LysIle Ala Lys Ile Ala Lys Lys Ile Leu 1 5 10 15 102 15 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 102 Phe Ala Phe Ala Lys Ile Ile Ala Lys IleAla Lys Lys Ile Ile 1 5 10 15 103 7 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 103 Phe Ala Leu Ala Leu Lys Ala 1 5 104 12 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 104 Lys Trp Lys Leu Ala Lys Lys Ala Leu AlaLeu Leu 1 5 10 105 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 105 PheAla Lys Ile Ile Ala Lys Ile Ala Lys Lys Ile 1 5 10 106 12 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 106 Phe Ala Leu Ala Leu Lys Ala Leu Lys LysAla Leu 1 5 10 107 8 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 107 PheAla Leu Lys Ala Leu Lys Lys 1 5 108 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 108 Lys Tyr Lys Lys Ala Leu Lys Lys Leu Ala Lys Leu Leu 1 5 10109 17 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 109 Phe Lys Arg LeuAla Lys Ile Lys Val Leu Arg Leu Ala Lys Ile Lys 1 5 10 15 Arg 110 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 110 Phe Ala Lys Leu Ala Lys LysAla Leu Ala Lys Leu Leu 1 5 10 111 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 111 Lys Ala Lys Leu Ala Lys Lys Ala Leu Ala Lys Leu Leu 1 5 10112 17 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 112 Lys Leu Ala LeuLys Leu Ala Leu Lys Ala Leu Lys Ala Ala Lys Leu 1 5 10 15 Ala 113 11 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 113 Phe Ala Lys Leu Leu Ala LysLeu Ala Lys Lys 1 5 10 114 13 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE114 Phe Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys Gly Leu 1 5 10 115 17PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 115 Phe Ala Leu Lys Ala LeuLys Lys Leu Lys Lys Ala Leu Lys Lys Ala 1 5 10 15 Leu 116 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 116 Val Ala Lys Leu Leu Ala LysLeu Ala Lys Lys Val Leu 1 5 10 117 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 117 Tyr Ala Lys Leu Leu Ala Lys Leu Ala Lys Lys Ala Leu 1 5 10118 17 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 118 Lys Leu Leu LysLeu Leu Leu Lys Leu Tyr Lys Lys Leu Leu Lys Leu 1 5 10 15 Leu 119 26 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 119 Phe Ala Val Gly Leu Arg AlaIle Lys Arg Ala Leu Lys Lys Leu Arg 1 5 10 15 Arg Gly Val Arg Lys ValAla Lys Asp Leu 20 25 120 16 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE120 Lys Leu Ala Lys Lys Leu Ala Lys Leu Ala Lys Leu Ala Lys Ala Leu 1 510 15 121 16 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 121 Lys Leu AlaLys Lys Leu Ala Lys Leu Ala Lys Leu Ala Lys Ala Leu 1 5 10 15 122 9 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 122 Lys Trp Lys Lys Leu Ala LysLys Trp 1 5 123 9 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 123 Lys TrpLys Lys Leu Ala Lys Lys Trp 1 5 124 17 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 124 Lys Leu Trp Lys Lys Trp Ala Lys Lys Trp Leu Lys Leu Trp LysAla 1 5 10 15 Trp 125 16 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 125Lys Leu Trp Lys Lys Trp Ala Lys Lys Trp Leu Lys Leu Trp Lys Ala 1 5 1015 126 11 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 126 Phe Ala Leu AlaLeu Lys Ala Leu Lys Lys Leu 1 5 10 127 11 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 127 Phe Ala Leu Ala Lys Ala Leu Lys Lys Ala Leu 1 510 128 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 128 Phe Ala Leu AlaLeu Lys Leu Ala Lys Lys Ala Leu 1 5 10 129 6 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 129 Phe Ala Leu Leu Lys Leu 1 5 130 10 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 130 Phe Ala Leu Ala Leu Lys Ala Leu Lys Lys1 5 10 131 10 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 131 Phe Ala LeuLys Ala Leu Lys Lys Ala Leu 1 5 10 132 11 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 132 Phe Ala Leu Leu Lys Ala Leu Lys Lys Ala Leu 1 510 133 4 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 133 Lys Trp Lys Lys1 134 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 134 Lys Trp Lys LysLeu 1 5 135 9 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 135 Lys Phe LysLys Leu Ala Lys Lys Phe 1 5 136 9 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 136 Lys Phe Lys Lys Leu Ala Lys Lys Trp 1 5 137 11 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 137 Phe Ala Leu Ala Leu Lys AlaLeu Lys Lys Ala 1 5 10 138 12 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE138 Phe Ala Leu Leu Lys Ala Leu Leu Lys Lys Ala Leu 1 5 10 139 11 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 139 Phe Ala Leu Ala Leu Lys LeuAla Lys Lys Leu 1 5 10 140 11 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE140 Leu Lys Lys Leu Ala Lys Leu Ala Leu Ala Phe 1 5 10 141 11 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 141 Val Ala Leu Ala Leu Lys AlaLeu Lys Lys Leu 1 5 10 142 10 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE142 Phe Ala Leu Ala Leu Lys Leu Lys Lys Leu 1 5 10 143 10 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 143 Phe Ala Leu Ala Leu Lys Ala Lys Lys Leu1 5 10 144 4 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 144 Phe Ala LeuAla 1 145 5 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 145 Trp Ala LeuAla Leu 1 5 146 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 146 GlyIle Gly Lys Phe Leu His Ala Ala Lys Lys Phe Ala Lys Ala Phe 1 5 10 15Val Ala Glu Ile Met Asn Ser 20 147 23 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 147 Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Lys Phe Ala Lys LysPhe 1 5 10 15 Ala Lys Phe Ala Phe Ala Phe 20 148 10 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 148 Lys Lys Val Val Phe Lys Val Lys Phe Lys1 5 10 149 10 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 149 Phe Lys ValLys Phe Lys Val Lys Val Lys 1 5 10 150 38 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 150 Leu Pro Lys Trp Lys Val Phe Lys Lys Ile Glu LysVal Gly Arg Asn 1 5 10 15 Ile Arg Asn Gly Ile Val Lys Ala Gly Pro AlaIle Ala Val Leu Gly 20 25 30 Glu Ala Lys Ala Leu Gly 35 151 23 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 151 Phe Ala Lys Lys Leu Ala LysLys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala Lys Leu Ala Lys LysLeu 20 152 15 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 152 Val Ala LysAla Leu Lys Ala Leu Leu Lys Ala Leu Lys Ala Leu 1 5 10 15 153 13 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 153 Val Ala Lys Phe Leu Ala LysPhe Leu Lys Lys Ala Leu 1 5 10 154 23 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 154 Val Ala Lys Lys Phe Ala Lys Lys Phe Lys Lys Phe Ala Lys LysPhe 1 5 10 15 Ala Lys Phe Ala Phe Ala Phe 20 155 19 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 155 Val Ala Lys Lys Leu Ala Lys Leu Ala LysLys Leu Ala Lys Leu Ala 1 5 10 15 Leu Ala Leu 156 15 PRT ARTIFICIALSEQUENCE SYNTHETIC SEQUENCE 156 Val Ala Lys Lys Leu Ala Lys Leu Ala LysLys Leu Leu Ala Leu 1 5 10 15 157 13 PRT ARTIFICIAL SEQUENCE SYNTHETICSEQUENCE 157 Val Ala Lys Leu Leu Ala Lys Ala Leu Lys Lys Leu Leu 1 5 10158 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 158 Val Ala Leu AlaLeu Lys Ala Leu Lys Lys Ala Leu Lys Lys Leu Lys 1 5 10 15 Lys Ala LeuLys Lys Ala Leu 20 159 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 159Val Ala Leu Ala Leu Lys Ala Leu Lys Lys Ala Leu Lys Lys Leu Lys 1 5 1015 Lys Ala Leu Lys Lys Ala Leu 20 160 23 PRT ARTIFICIAL SEQUENCESYNTHETIC SEQUENCE 160 Val Ala Leu Ala Leu Lys Ala Leu Lys Lys Leu AlaLys Lys Leu Lys 1 5 10 15 Lys Leu Ala Lys Lys Ala Leu 20 161 23 PRTARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 161 Val Ala Leu Ala Leu Lys AlaLeu Lys Lys Leu Leu Lys Lys Leu Lys 1 5 10 15 Lys Leu Ala Lys Lys AlaLeu 20 162 23 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 162 Phe Ala LysLys Leu Ala Lys Lys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala LysLeu Ala Leu Ala Leu 20 163 30 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE163 Phe Ala Lys Lys Leu Ala Lys Lys Leu Lys Lys Leu Ala Lys Lys Leu 1 510 15 Ala Lys Leu Ala Leu Ala Leu Lys Ala Leu Ala Leu Lys Ala 20 25 30164 18 PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 164 Phe Ala Lys LysLeu Ala Lys Lys Leu Lys Lys Leu Ala Lys Lys Leu 1 5 10 15 Ala Lys 165 13PRT ARTIFICIAL SEQUENCE SYNTHETIC SEQUENCE 165 Phe Ala Lys Leu Leu AlaLeu Ala Leu Lys Lys Ala Leu 1 5 10

What is claimed is:
 1. An isolated peptide comprising phenylalanine,leucine, alanine, and lysine residues, wherein: the peptide is about 5to about 23 amino acids in length; and the peptide is at least about 50%phenylalanine, leucine, alanine, and lysine residues.
 2. The peptide ofclaim 1, wherein the peptide is about 5 to about 20 amino acids inlength.
 3. The peptide of claim 1, wherein the peptide consistsessentially of phenylalanine, leucine, alanine, and lysine residues. 4.The peptide of claim 1, wherein the peptide consists of phenylalanine,leucine, alanine, and lysine residues.
 5. The peptide of claim 1,wherein the first amino acid of the peptide is valine.
 6. The peptide ofclaim 1, wherein the peptide is at least about 70% identical to SEQ IDNO:2, SEQ ID NO:16, SEQ ID NO:126, SEQ ID NO:4, SEQ ID NO:14, SEQ IDNO:17, SEQ ID NO:25, SEQ ID NO:43, SEQ ID NO:75, SEQ ID NO:84, SEQ IDNO:115, or SEQ ID NO:132.
 7. The peptide of claim 1, further defined asSEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ IDNO:8, SEQ ID NO:10, SEQ ID NO:4l, SEQ ID NO:12, SEQ ID NO:13, SEQ IDNO:14, SEQ ID NO:1 15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ IDNO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:26, SEQ IDNO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ IDNO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:41, SEQ IDNO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:50, SEQ ID NO:51, SEQ IDNO:52, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ IDNO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:65, SEQ ID NO:66, SEQ IDNO:67, SEQ ID NO:68, SEQ ID NO:71, SEQ ID NO:74, SEQ ID NO:75, SEQ IDNO:77, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:84, SEQ ID NO:85, SEQ IDNO:86, SEQ ID NO:87, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ IDNO:93, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:112, SEQ ID NO:1 15, SEQID NO:1 16, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129,SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:137, SEQ ID NO:138, SEQ IDNO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQID NO:144, SEQ ID NO:145, SEQ ID NO:152, SEQ ID NO:159, SEQ ID NO:162,SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165.
 8. A method forinhibiting the growth of cancer cells, the method comprising contactingthe cancer cells with a peptide; wherein: the peptide comprisesphenylalanine, leucine, alanine, and lysine residues; the peptide isabout 5 to about 23 amino acids in length; and the peptide comprises atleast about 50% phenylalanine, leucine, alanine, and lysine residues. 9.The method of claim 8, wherein the peptide is about 5 to about 20 aminoacids in length.
 10. The method of claim 8, wherein the peptide consistsessentially of phenylalanine, leucine, alanine, and lysine residues. 11.The method of claim 8, wherein the peptide consists of phenylalanine,leucine, alanine, and lysine residues.
 12. The method of claim 8,wherein the first amino acid of the peptide is valine.
 13. The method ofclaim 8, wherein the peptide is at least about 70% identical to SEQ IDNO:2, SEQ ID NO:16, SEQ ID NO:126, SEQ ID NO:4, SEQ ID NO:14, SEQ IDNO:17, SEQ ID NO:25, SEQ ID NO:43, SEQ ID NO:75, SEQ ID NO:84, SEQ IDNO:1 15, or SEQ ID NO:132.
 14. The method of claim 8, wherein thepeptide is SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:8, SEQ ID NO:1, SEQ IDNO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ IDNO:20, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:29, SEQ ID NO:30, SEQ IDNO:32, SEQ ID NO:35, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:56, SEQ IDNO:57, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:75, SEQ IDNO:86, SEQ ID NO:152, or SEQ ID NO:162.
 15. The method of claim 8,wherein the contacting step is performed in vivo, in vitro, topically,orally, transdermally, or by systemic injection.
 16. The method of claim8, wherein the contacting step is performed in vivo, and theconcentration of the peptide is about 1 mg/kg and about 100 mg/kg. 17.The method of claim 8, wherein the contacting step is performed in vitroor topically, and the concentration of the peptide is at least about 0.1μM.
 18. The method of claim 8, wherein the cancer cells are lymphoma,leukemia, melanoma, squamous, or carcinoma cells.
 19. The method ofclaim 8, wherein the cancer cells are breast cancer cells, colon cancercells, lung cancer cells, cervical cancer cells, corneal cancer cells,epitheleal cancer cells, or prostate cancer cells.
 20. The method ofclaim 8, whereby the growth of cancer cells is reduced by at least about10% as compared to the growth of cancer cells without treatment with thepeptide.
 21. A method of treating an animal, the method comprisingadministering to the animal a peptide, wherein: the animal containscancer cells; the peptide comprises phenylalanine, leucine, alanine, andlysine residues; the peptide is about 5 to about 23 amino acids inlength; and the peptide comprises at least about 50% phenylalanine,leucine, alanine, and lysine residues.
 22. The method of claim 21,wherein the peptide is about 5 to about 20 amino acids in length. 23.The method of claim 21, wherein the peptide consists essentially ofphenylalanine, leucine, alanine, and lysine residues.
 24. The method ofclaim 21, wherein the peptide consists of phenylalanine, leucine,alanine, and lysine residues.
 25. The method of claim 21, wherein thefirst amino acid of the peptide is valine.
 26. The method of claim 21,wherein the peptide is at least about 70% identical to SEQ ID NO:2, SEQID NO:16, SEQ ID NO:126, SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:17, SEQ IDNO:25, SEQ ID NO:43, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:1 15, or SEQID NO:132.
 27. The method of claim 21, wherein the peptide is SEQ IDNO:1, SEQ ID NO:2, SEQ ID NO:8, SEQ ID NO:1 1, SEQ ID NO:13, SEQ IDNO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ IDNO:25, SEQ ID NO:26, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ IDNO:35, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:56, SEQ ID NO:57, SEQ IDNO:58, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:75, SEQ ID NO:86, SEQ IDNO:152, or SEQ ID NO:162.
 28. The method of claim 21, wherein thecontacting step is performed in vivo, topically, orally, ortransdermally.
 29. The method of claim 21, wherein the contacting stepis performed in vivo, and the concentration of the peptide is about 0.1mg/kg to about 100 mg/kg.
 30. The method of claim 21, wherein thecontacting step is performed topically, and the concentration of thepeptide is at least about 0.1 μM.
 31. The method of claim 21, whereinthe cancer cells are lymphoma, leukemia, melanoma, or carcinoma cells.32. A method for inhibiting the growth of microbial cells, the methodcomprising contacting the microbial cells with a peptide; wherein: thepeptide comprises phenylalanine, leucine, alanine, and lysine residues;the peptide is about 5 to about 23 amino acids in length; and thepeptide comprises at least about 50% phenylalanine, leucine, alanine,and lysine residues.
 33. The method of claim 32, wherein the peptide isabout 5 to about 20 amino acids in length.
 34. The method of claim 32,wherein the peptide consists essentially of phenylalanine, leucine,alanine, and lysine residues.
 35. The method of claim 32, wherein thepeptide consists of phenylalanine, leucine, alanine, and lysineresidues.
 36. The method of claim 32, wherein the first amino acid ofthe peptide is valine.
 37. The method of claim 32, wherein the peptideis at least about 70% identical to SEQ ID NO:2, SEQ ID NO:16, SEQ IDNO:126, SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:25, SEQ IDNO:43, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:115, or SEQ ID NO:132. 38.The method of claim 32, wherein the peptide is SEQ ID NO:1, SEQ ID NO:2,SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:11, SEQID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ IDNO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ IDNO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:30, SEQ IDNO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ IDNO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:50, SEQ IDNO:51, SEQ ID NO:52, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ IDNO:58, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ IDNO:68, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:80, SEQ IDNO:81, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:93, SEQ IDNO:106, SEQ ID NO:108, SEQ ID NO:1 12, SEQ ID NO:1 15, SEQ ID NO:126,SEQ ID NO:128, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, or SEQ IDNO:165.
 39. The method of claim 32, wherein the peptide is SEQ ID NO:2,SEQ ID NO:10, SEQ ID NO:6 1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16,SEQ ID NO:175 SEQ ID NO:25, SEQ ID NO:30, SEQ ID NO:355 SEQ ID NO:583SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:845SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:106, SEQ ID NO:1085 SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:126, SEQ ID NO:1285, SEQ ID NO:131, SEQ IDNO:143, SEQ ID NO:163, or SEQ ID NO:165.
 40. The method of claim 32,wherein the contacting step is performed in vivo, in vitro, topically,orally , transdermally, or by systemic injection.
 41. The method ofclaim 32, wherein the contacting step is performed in vivo, and theconcentration of the peptide is about 0.1 mg/kg to about 100 mg/kg. 42.The method of claim 32, wherein the contacting step is performed invitro or topically, and the concentration of the peptide is at leastabout 0.1 μM.
 43. The method of claim 32, whereby the growth ofmicrobial cells is reduced by at least about 50% as compared to thegrowth of microbial cells without treatment with the peptide.
 44. Themethod of claim 32, wherein the microbial cells are bacterial cells. 45.The method of claim 44, wherein the bacterial cells are Staphylococcus,Stapholococcus aureus, Pseudomonas, Pseudomonas aeruginosa, Chlamydia,or Escherichia cells.
 46. The method of claim 44, wherein the bacterialcells are gram positive bacteria, gram negative bacteria, ormycobacteria.
 47. The method of claim 32, wherein the microbial cellsare fungal cells.
 48. The method of claim 47, wherein the fungal cellsare Candida, Candida albicans, Saccharomyces, Saccharomyces cerevisiae,Schizosaccharomyces, or Schizosaccharomyces pombe cells.
 49. The methodof claim 32, wherein the microbial cells are protozoa.
 50. The method ofclaim 49, wherein the protozoa are Trypanosoma cruzi or Plasmodiumfalciparum.
 51. The method of claim 32, wherein the microbial cells areintracellular organisms.
 52. The method of claim 32, wherein themicrobial cells are viruses.